Methods and kits for assessing neurological function and localizing neurological lesions

ABSTRACT

The invention provides methods and kits for detecting, screening, quantifying or localizing the etiology for reduced or impaired cranial nerve function or conduction; localizing a central nervous system lesion; detecting, diagnosing or screening for increased intracranial pressure, pressure or disruption of central nervous system physiology as seen with concussion; or detecting, diagnosing, monitoring progression of or screening for a disease or condition featuring increased intracranial pressure or concussion by tracking eye movement of the subject. The invention also provides methods and kits useful for detecting, screening for or quantitating disconjugate gaze or strabismus, useful for diagnosing a disease characterized by disconjugate gaze or strabismus in a subject, useful for detecting, monitoring progression of or screening for a disease or condition characterized by disconjugate gaze or strabismus in a subject or useful for quantitating the extent of disconjugate gaze or strabismus. Further, the invention provides methods for assessing or quantifying structural and non-structural traumatic brain injury or diagnosing a disease characterized by or featuring structural and non-structural traumatic brain injury.

FIELD OF THE INVENTION

The present invention relates to methods and kits for assessingphysiologic function of the cranial nerves II, III, IV and VI, screeningfor, diagnosing, and quantitating the extent of elevated intracranialpressure, transtentorial herniation, concussion, normal pressurehydrocephalus, posterior fossa mass effect, optic neuropathy,neurodegenerative diseases, and diagnosing, localizing and monitoringprogression of intracranial lesions and disease processes. The presentinvention also relates to methods and kits for assessing or quantitatingconjugacy or disconjugacy of gaze or strabismus and for screening for,diagnosing, and assessing neurological diseases characterized by orfeaturing the same. In addition, the present invention relates tomethods and kits for assessing or quantitating structural andnon-structural traumatic brain injury and for screening for, diagnosing,and assessing the same.

BACKGROUND OF THE INVENTION Eye Movement Tracking

Automated eye movement tracking has been used for marketing andadvertising research, the development of assistive devices for immobileindividuals, and for video games. Spatial calibration of the devicerequires the subject to have relatively intact ocular motility thatimplies function of cranial nerves II (optic), III (oculomotor), IV(trochlear) and VI (abducens) and their associated nuclei as well assufficient cerebral function to enable cognition and volition forcalibration. Calibrated eye movement tracking has been utilized todetect cognitive impairment secondary to axonal shearing after mildtraumatic brain injury (Lee, Brain research. 2011; 1399:59-65; Contreraset al., Brain Research 2011; 1398:55-63 and Maruta et al., The Journalof Head Trauma Rehabilitation 2010; 25(4):293-305).

Others have successfully demonstrated the clinical applications of eyemovement data (Lee et al., Brain Research. 2011; 1399:59-65; Contreraset al., Brain Research 2011; 1398:55-63; Maruta et al., The Journal ofHead Trauma Rehabilitation 2010; 25(4):293-305). Trojano et al., JNeurol 2012; (published online; ahead of print) recently describeduncalibrated eye movement measurements in a population of minimallyconscious and persistently vegetative patients. They report data from 11healthy control subjects evaluating chronic disorders of consciousness,not acute changes in intracranial pressure. They sample eye movements at60 Hz rather than 500 Hz, effectively reducing the power of their data100-fold, and they report differences in on-target and off-targetfixations between the groups without spatially calibrated data.Moreover, they use static stimuli moving in a quasi-periodic way.

Elevated Intracranial Pressure

If untreated, acute elevations in intracranial pressure (ICP) due tohydrocephalus, brain injury, stroke, or mass lesions can result inpermanent neurologic impairment or death. Hydrocephalus, the most commonpediatric neurosurgical condition in the world, has been well studied asa model for understanding the impact of elevated ICP. The visualdisturbances and diplopia associated with hydrocephalus were firstdescribed by Hippocrates in approximately 400 B.C. (Aronyk, NeurosurgClin N Am. 1993; 4(4):599-609). Papilledema, or swelling of the opticdisc, and its association with elevated ICP was described by Albrechtvon Graefe in 1860 (Pearce, European neurology 2009; 61(4):244-249). Inthe post-radiographic era, acute and chronic pathology of the opticnerve and disc (cranial nerve II), and of ocular motility (cranialnerves III, IV and VI) are well characterized in hydrocephalic children(Dennis et al., Arch Neurol. October 1981; 38(10):607-615; Zeiner etal., Childs Nerv Syst. 1985; 1(2):115-122 and Altintas et al., Graefe'sarchive for clinical and experimental ophthalmology=Albrecht von GraefesArchiv fur klinische and experimentelle Ophthalmologic. 2005; 243 (12):1213-1217). Visual fields may be impaired in treated hydrocephalus(Zeiner et al., Childs Nerv Syst. 1985; 1(2):115-122), and there isincreased latency in light-flash evoked responses in acutelyhydrocephalic children relative to their post treatment state (Sjostromet al., Childs Nerv Syst. 1995; 11(7):381-387). Clinically apparentdisruption of ocular motility may precede computed tomography (CT)findings in some acute hydrocephalics (Tzekov et al., PediatricNeurosurgery 1991; 17(6):317-320 and Chou et al., Neurosurgery Clinicsof North America 1999; 10(4):587-608).

Several potential mechanisms may contribute to cranial nerve dysfunctiondue to hydrocephalus. The optic nerve (II) is most frequently analyzedbecause it can be visualized directly with ophthalmoscopy, andindirectly with ultrasound. Edema of the optic nerve appears earlierthan ocular fundus changes, and resolves after treatment of elevated ICP(Gangemi et al., Neurochirurgia 1987; 30(2):53-55). Fluctuating elevatedneural pressure leads to impaired axonal transport along the optic nerveafter as little as 30 minutes in a rabbit model (Balaratnasingam et al.,Brain Research 2011; 1417:67-76). Axoplasmic flow stasis andintraneuronal ischemia may occur in the optic nerve exposed tochronically elevated ICP (Lee et al., Current Neurology and NeuroscienceReports. Feb. 23, 2012).

At present, the diagnosis of elevated intracranial pressure relies onhistory, physical exam, radiographic imaging, and possibly directinvasive assessment of the subarachnoid space or structures contiguouswith it via cannulated needle tap of a shunt or monitoring deviceplacement. Chemical dilatation of the pupil to assess for papilledemamay be unpleasant for the examinee, relies on the experience of theexaminer and obfuscates further examination of the pupillary reflex.Papilledema is not always a sensitive marker for hydrocephalus, and inone study was present in as few as 14% of patients with a shuntmalfunction (Nazir et al., J Aapos 2009; 13(1):63-66) consistent withthe relatively short intracranial course of II relative to cranialnerves III and IV. Compartmentalization of subarachnoid spaces ishypothesized to explain why papilledema may be present in a patientwithout elevated ICP, and not occur in patients with elevated ICP(Killer et al., Clinical & Experimental Ophthalmology 2009;37(5):444-447).

Conjugacy of Eye Movement

It is conceivable that the process of spatial calibration may maskdeficits in ocular motility. If there is a persistent and replicableweakness in movement of an eye, the camera will interpret the eye'sability to move in the direction of that weakness as the full potentialrange of motion in that direction due to the calibration process. Inother words if the subject is directed to look at a position butconsistently only moves halfway there, the calibration process willaccount for that when tracking subsequent eye movements and interpretmovements to the halfway point as occurring at the full range of normalmotion. If during calibration one eye only makes it halfway to thetarget, but the other eye is fully there, the camera will interpret botheyes as being together when one performs half the eye movement as theother. Thus binocular spatial calibration may preclude detection ofdisconjugate gaze unless each eye is calibrated separately using adichoptic apparatus (Schotter, et al., PLoS One, 2012; 7: e35608).

Conjugate gaze is the motion of both eyes in the same direction at thesame time. The conjugate gaze is believed to be controlled by thefollowing four different mechanisms: the saccadic system that allows forvoluntary direction of the gaze, the pursuit system that allows thesubject to follow a moving object, the optokinetic system that restoresgaze despite movements of the outside world, and the vestibulo-ocularreflex system (VOR system) that corrects for the movements of the headto preserve the stable visual image of the world.

Disconjugate gaze or strabismus is a failure of the eyes to turntogether in the same direction. Normal coordinated movements of the eyesproduces conjugate gaze, in which the eyes are aligned for binocular3-dimensional vision. Misalignment results in loss of this vision. Withthe visual axis of each eye fixated on a different point, diplopia (ordouble vision) usually results and may be perceived as a blurred imageif the two images are very closely aligned. However, if the image fromthe weaker eye is suppressed by higher cortical centers, there is onlyone image with loss of visual acuity (or a blurred image). Pathologyusually resides either in the oculomotor muscles or their neuronalpathways including the medial longitudinal fasiculus, the paramedianpontine reticular formation, the medullary reticular formation, thesuperior colliculus, or the cranial nerves III, IV, or VI or theirnuclei.

Assessment of eye movement conjugacy is commonly performed by primarycare physicians, neurologists, ophthalmologists, neurosurgeons,emergency medicine doctors, and trauma surgeons to rapidly assess globalneurologic functioning. In stable patients, ophthalmologists andneurologists perform more detailed examination to assess the alignmentof the eyes such as the cover test and Hirschberg corneal reflex test.Other tests used to assess binocular conjugacy include the Titmus HouseFly test, Lang's stereo test, the Hess screen, red-filter test, Maddoxrod evaluation and Lancaster red-green test. In young children, who maybe less cooperative with an examiner, binocular gaze conjugacy may onlybe assessable with simpler algorithms, such as following an objectmoving in a set trajectory (Cavezian, et al., Res Dev Disabil., 2010;31: 1102-1108). When such tests are performed in conjunction with theremainder of the neurophthalmic and physical evaluation, one canlocalize neurologic lesions and quantitate ocular motility deficits withgreat accuracy. Despite this capability, these tests are not usedroutinely in the emergency setting due to the need for a trainedpractitioner to administer them, the requirement for sophisticatedequipment, and the urgent nature of many neurologic disorders.

Assessment of binocular gaze conjugacy in primates for research purposesis performed with the magnetic search coil technique requiring coilsimplanted into the bulbar conjunctiva (Schultz, et al., J Neurophysiol.,2013; 109: 518-545). This technique was first described by Fuchs andRobinson in 1966 (Fuchs, et al., J Appl Physiol., 1966; 21: 1068-1070)and can also be performed in humans fitted with sclera search coilsdesigned specifically for tracking eye movements.

Experimentally, spatially calibrated eye movement tracking using theBouis oculometer (Bach, et al., J Neurosci Methods, 1983; 9: 9-14),which requires that the head is rigidly fixed, shows that healthy sevenyear old children have increased disconjugacy of eye movement duringsaccades relative to adults while both perform a reading task (Bucci, etal., Vision Res., 2006; 46: 457-466). Research on disconjugacy duringreading can be performed using a dichoptic apparatus in which theindividual eyes are spatially calibrated separately and presented withstimuli to assess movements separately for simultaneous comparison toeach other (Schotter, et al., PLoS One, 2012; 7: e35608).

Brain Injury

One of the problems associated with the study of outcomes after braininjury, is the heterogeneous nature of such injury in terms of etiology,anatomic sequelae, and physiologic and psychologic impact. The etiologyof injury affects the anatomic sequelae and ranges from globalmechanisms such as acceleration/deceleration and blast, to potentiallymore focal mechanisms such as blunt impact and penetrating trauma. Someinjury mechanisms result in structural changes to the brain that can bevisualized using conventional imaging such as MM and CT scan, whileother injuries appear radiographically normal.

Acceleration/deceleration injury may result in structurally visiblecoup/contrecoup injuries and less visible diffuse axonal injury (DAI)(Cecil, et al., Journal of Neurosurgery, 1998; 88: 795-801)Acceleration/deceleration is also thought to be one of the potentialmechanisms for concussion which is the most common form of civilianradiographically normal brain injury (Bayly, et al., Journal ofNeurotrauma, 2005; 22: 845-856; Daneshvar, et al., Physical Medicine andRehabilitation Clinics of North America, 2011; 22: 683-700). Concussionis brain injury, most often resulting from blunt impact, in the absenceof structural abnormality by conventional radiographic imaging such ascomputed tomography (CT) scan (McCrory, et al., The Physician and SportsMedicine, 2009; 37: 141-159). Concussion may include transient loss ordisruption of neurologic function. The term “subconcussion” may be usedto describe the sequelae of brain injury in the absence of transientloss or disruption of neurologic function. Both concussion andsubconcussion as well as blast injury may be termed “non-structural”brain injury.

Blast injury resembles blunt impact brain injury in that both may beassociated with radiographically apparent cerebral edema andintracranial hemorrhage, however with blast injury the edema onset maybe more rapid and severe, and there is greater likelihood of clinicalvasospasm (Armonda, et al., Neurosurgery, 2006; 59: 1215-1225). Blastinjury is very frequently radiographically normal, yet mild or moderateblast injury is strongly associated with post-traumatic stress disorderand other cognitive dysfunctions (Cernak, et al., The Journal of Trauma,2001; 50: 695-706). The actual cause of blast brain injury is suspectedto be multifactorial and often results in DAI (Leung, et al., Mol CellBiomech, 2008; 5: 155-168). A shock wave resulting from pressure changescaused by the explosion impacts both cranial and non-cranial structures(Courtney, et al., Medical Hypotheses, 2009; 72: 76-83; Bauman, et al.,Journal of Neurotrauma, 2009; 26: 841-860). Blast injury affects thebrain through several mechanisms: primary brain injury caused byblast-wave induced changes in atmospheric pressure directly impactingthe brain; secondary injury resulting from objects put in motion by theblast that impact the head, and tertiary injury resulting from thevictim striking the head upon falling or being propelled into a solidobject (Warden, The Journal of Head Trauma Rehabilitation, 2006; 21:398-402).

Blunt impact and penetrating trauma can result in both diffuse and focalinjury. One mechanism by which focal brain injury leads to neurologicdamage is cortical spreading depression (Hartings, et al., Journal ofNeurotrauma, 2009; 26: 1857-1866), which is currently only thoughtmeasurable using invasive means.

Brain injury may be associated with short term sequelae includingheadaches and memory problems, and longer term problems includingdementia, Parkinsonism and motor-neuron disease (Daneshvar, et al.,Physical Medicine and Rehabilitation Clinics of North America, 2011; 22:683-700). Both concussion and mild blast injury may be associated withpost-traumatic stress disorder and cognitive impairment (Taber, et al.,The Journal of Neuropsychiatry and Clinical Neurosciences, 2006; 18:141-145). Clinical tests for concussion show poor test reliability(Broglio, et al., Journal of Athletic Training, 2007; 42: 509-514) andthus concussion remains a diagnosis that is difficult to treat becauseit is difficult to detect. Traumatic brain injury can impact eyemovement through a multitude of mechanisms including direct compressionof cranial nerves, trauma to cranial nerves, injury to cranial nervenuclei and supranuclear impacts.

Many cases of trauma result in elevated intracranial pressure. Ifuntreated, acute elevations in intracranial pressure (ICP) due to braininjury can result in permanent neurologic impairment or death. Doublevision and other ocular disturbances associated with elevated ICP werefirst described by Hippocrates in approximately 400 B.C. (Aronyk,Neurosurgery Clinics of North America, 1993; 4: 599-609). Papilledema,and its association with elevated ICP was described by Albrecht vonGraefe in 1860 (Pearce, European Neurology, 2009; 61: 224-249). In thepost-radiographic era, acute and chronic pathology of the optic nerveand disc, and of ocular motility are well characterized in people withelevated ICP (Dennis, et al., Archives of Neurology, 1981; 38: 607-615;Zeiner, et al., Child's Nerv. Syst., 1985; 1: 115-122; Altintas, et al.,Graefe's Archive for Clinical and Experimental Ophthalmology, 2005; 243:1213-1217). Clinically apparent disruption of ocular motility mayprecede computed tomography (CT) findings in some subjects with acutelyelevated ICP (Tzekov, et al., Pediatric Neurosurgery, 1991; 17: 317-320;Chou, et al., Neurosurgery Clinics of North America, 1999; 10: 587-608).

Several potential mechanisms may contribute to cranial nerve dysfunctiondue to elevated intracranial pressure. The IIIrd nerve (oculomotor) maybe directly compressed by the medial aspect of the temporal lobe withfrontal or temporal mass lesions, or diffuse supratentorial mass effect.The VIth nerve (abducens) is anatomically vulnerable to infratentorialmass effect at the prepontine cistern and to hydrocephalus from stretchas it traverses the tentorial edge.

Elevated intracranial pressure slows axoplasmic transport along cranialnerves (Balarratnasingam, et al., Brain Research, 2011; 1417: 67-76).The optic nerve (II) is most frequently analyzed because it can bevisualized directly with ophthalmoscopy, and indirectly with ultrasound.Edema of the optic nerve appears earlier than ocular fundus changes, andresolves after treatment of elevated ICP Gangemi, et al.,Neurochirurgia, 1987; 30: 53-55). Fluctuating elevated neural pressureleads to impaired axonal transport along the optic nerve after as littleas 30 minutes in a rabbit model (Balarratnasingam, et al., BrainResearch, 2011; 1417: 67-76). Axoplasmic flow stasis and intraneuronalischemia may occur in the optic nerve exposed to chronically elevatedICP (Lee, et al., Current Neurology and Neuroscience Reports, 2012).Among the nerves impacting ocular motility, the trochlear nerve (IV),followed by oculomotor (III) and then abducens (VI), has the greatestlength of exposure to the subarachnoid space with the narrowestdiameter, and thus may be most vulnerable to a pressure induced palsy(Hanson, et al., Neurology, 2004; 62: 33-36; Adler, et al., Journal ofNeurosurgery, 2002; 96: 1103-1113). The optic nerve (II) hasapproximately the same length of exposure as the abducens (Murali, etal., in Head Injury (ed. Paul Cooper and John Golfinos) (McGraw-Hill,2000)), and thus papilledema, or swelling of the optic disc apparent onophthalmoscopic examination may be a relatively late indicator ofelevated ICP (Killer, et al., Clinical & Experimental Ophthalmology,2009; 37: 444-447; Nazir, et al., J Aapos, 2009; 13: 62-66). Papilledemais not always a sensitive marker for hydrocephalus leading to elevatedICP, and in one study was present in as few as 14% of patients with ashunt malfunction (Nazir, et al., J Aapos, 2009; 13: 62-66) consistentwith the relatively short intracranial course of II compared to cranialnerves III and IV. Compartmentalization of subarachnoid spaces ishypothesized to explain why papilledema may be present in a patientwithout elevated ICP, and not occur in patients with elevated ICP(Killer, et al., Clinical & Experimental Ophthalmology, 2009; 37:444-447).

All publications, patent applications, patents and other referencematerial mentioned are incorporated by reference in their entirety, forinstance, Patent Cooperation Treaty Application No. PCT/US2013/033672filed Mar. 25, 2013, and U.S. provisional application 61/881,014, filedSep. 23, 2013. In addition, the materials, methods and examples are onlyillustrative and are not intended to be limiting. The citation ofreferences herein is not to be construed as an admission that thereferences are prior art to the present invention.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides methods for localizing acentral nervous system lesion in a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject;    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye; and    -   e) Localizing the central nervous system lesion.

The lesion may feature increased intracranial pressure, and the lesionmay be, for instance, subsequent to a trauma, a cerebrovascular accident(CVA), an aneurysm or other vascular lesion, a tumor whether malignantor benign, an infectious process, an inflammatory disease, a disruptionof venous drainage, a pseudotumor, neurodegenerative disease,hydrocephalus or idiopathic. Localizing the central nervous systemlesion may be performed, for instance, by determining the side of thebrain that is experiencing increased intracranial pressure. The side ofthe brain that is experiencing increased intracranial pressure may bedetermined, for instance, by determining eye movement on that side ofthe brain that is altered compared to the other side or that is alteredcompared to that subject's baseline eye movement or to a controlsubject's eye movement.

In a second aspect, the invention provides methods for diagnosing acentral nervous system lesion in a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

The lesion may feature increased intracranial pressure, and the lesionmay be, for instance, subsequent to a trauma, a cerebrovascular accident(CVA), an aneurysm or other vascular lesion, a tumor whether malignantor benign, an infectious process, an inflammatory disease, a disruptionof venous drainage, a pseudotumor, hydrocephalus or idiopathic.

In a third aspect, the invention provides methods for assessing andquantitating central nervous system integrity in a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a fourth aspect, the invention provides methods for detecting orscreening for reduced or impaired cranial nerve function or conductionin a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

The cranial nerve may be, for instance, one or more of II, III, IV orVI. The reduced or impaired cranial nerve function or conduction may beunilateral or bilateral and may be caused all or in part by increasedintracranial pressure, and it may be caused all or in part by alocalized or diffuse lesion or disease process. The reduced function ofthe cranial nerve may be due to pathology impacting the nerve itself,its associated nucleus or supranuclear inputs including, for instance,lesions affecting the cerebral cortex.

In a fifth aspect, the invention provides methods for detecting,diagnosing or screening for increased intracranial pressure in a subjectby

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

The increased intracranial pressure may be, for instance, 10%, 20%, 30%,50%, 100%, 200%, 300% or more greater than normal.

In a sixth aspect, the invention provides methods for detecting,diagnosing, monitoring progression of or screening for a disease orcondition featuring increased intracranial pressure by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

The disease or condition featuring increased intracranial pressure maybe, for instance, a trauma, cerebrovascular accident (CVA), an aneurysmor other vascular lesion, a tumor whether malignant or benign, aninfectious process, an inflammatory disease, a disruption of venousdrainage, a pseudotumor, hydrocephalus or idiopathic.

In a seventh aspect, the invention provides methods for detecting,diagnosing or screening for concussion by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a eighth aspect, the invention provides methods for detecting,diagnosing or screening for transtentorial herniation by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a ninth aspect, the invention provides methods for quantifying theseverity of normal pressure hydrocephalus, detecting or screening forshunt malfunction or optimizing valve pressure for treating normalpressure hydrocephalus by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a tenth aspect, the invention provides methods for detecting orevaluating posterior fossa mass effect by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In an eleventh aspect, the invention provides methods for detecting,screening for or diagnosing a disorder that impedes conductance throughthe optic disc or optic nerve by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a twelfth aspect, the invention provides methods for quantitating theextent of impairment of the entire central nervous system by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

The integrity of the central nervous system may be impaired by, forinstance, trauma, stroke, a neurodegenerative disease, inflammation, aninfectious process, a neoplastic process, vascular disease, anautoimmune disease, a genetic disorder or other causes. This aspect ofthe invention provides methods for quantitating the extent of global CNSimpairment. This aspect of the invention takes advantage of the factthat more that 55% of the brain contributes to vision and visual acuity.

In a thirteenth aspect the invention provides methods for quantitatingor assessing cognitive integrity by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing eye movement of a first eye of the subject to eye        movement of a second eye of the subject; and    -   d) Identifying the subject as having eye movement of a first eye        that is significantly different from eye movement of a second        eye.

In a fourteenth aspect, the invention provides a kit useful fordetecting or screening for reduced or impaired cranial nerve function orconduction, useful for detecting, diagnosing or screening for increasedintracranial pressure, or useful for detecting, diagnosing, monitoringprogression of or screening for a disease or condition featuringincreased intracranial pressure containing a device for tracking eyemovement, one or more means for analyzing eye movement tracking datasuch as, for instance, an algorithm or computer program, andinstructions. Processing eye movement observations, making measurementsof eye movement observations, determining distributions of valuesmeasured and performing statistical tests may all be accomplished usingsuitable computer software that may be included in such a kit.

In a fifteenth aspect, the invention provides methods for assessingconjugacy or disconjugacy of eye movement in a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing the x or y Cartesian coordinates at any time point        for the eye movement of a first eye of the subject to the        respective x or y Cartesian coordinates at the time point for        the eye movement of a second eye of the subject;    -   d) Providing a sum of the differences between all of the x or y        coordinates of the first eye compared to the second eye over the        time tested or providing a sum of the differences in x or y        coordinates of the first eye compared to the second eye over the        time tested or both; and, optionally    -   e) Providing a total sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested.

In a sixteenth aspect, the invention provides methods for diagnosing adisease characterized by or featuring disconjugate gaze or strabismus ina subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing the x or y Cartesian coordinates at any time point        for the eye movement of a first eye of the subject to the        respective x or y Cartesian coordinates at the time point for        the eye movement of a second eye of the subject;    -   d) Providing a sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested or providing a sum of the differences in the x or y        coordinates of the first eye compared to the second eye over the        time tested or both; and, optionally    -   e) Providing a total sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested.

In some instances, the disease may be one of trauma, hydrocephalus,demyelination, inflammation, infection, degenerative disease,neoplasm/paraneoplastic syndrome, metabolic disease including diabetes,or vascular disruption such as stroke, hemorrhage or aneurysm formation.The disease may also be an ophthalmologic disease such asconjunctivitis, ophthalmoplegia, ocular injury or other diseases. Insome instances, the subject suffering from the disease may have a totalsum of the differences between the x or y coordinates of the first eyecompared to the second eye over the time tested that is 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, or two, three, four,five, six, eight, ten or more times greater than the total sum of thedifferences between the x or y coordinates of the first eye compared tothe second eye over the time tested in a healthy control or in areference value based upon one or more healthy controls or based uponthe subject at a time before the disease.

In a seventeenth aspect, the invention provides methods for assessingand quantitating central nervous system integrity in a subject by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing the x or y Cartesian coordinates at any time point        for the eye movement of a first eye of the subject to the        respective x or y Cartesian coordinates at the time point for        the eye movement of a second eye of the subject;    -   d) Providing a sum of the differences between all of the x or y        coordinates of the first eye compared to the second eye over the        time tested or providing a sum of the differences in the x or y        coordinates of the first eye compared to the second eye over the        time tested or both; and, optionally    -   e) Providing a total sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested.

In a eighteenth aspect, the invention provides methods for detecting,monitoring progression of or screening for a disease or conditioncharacterized by disconjugate gaze or strabismus by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing the x or y Cartesian coordinates at any time point        for the eye movement of a first eye of the subject to the        respective x or y Cartesian coordinates at the time point for        the eye movement of a second eye of the subject;    -   d) Providing a sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested or providing a sum of the differences in y        coordinates of the first eye compared to the second eye over the        time tested or both; and, optionally    -   e) Providing a total sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested.

In some instances, the disease may be one of trauma, hydrocephalus,demyelination, inflammation, infection, degenerative disease,neoplasm/paraneoplastic syndrome, metabolic disease including diabetes,or vascular disruption such as stroke, hemorrhage or aneurysm formation.The disease may also be an ophthalmologic disease such asconjunctivitis, ophthalmoplegia, ocular injury or other diseases. Insome instances, the subject suffering from the disease may have a totalsum of the differences between the x or y coordinates of the first eyecompared to the second eye over the time tested that is 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, or two, three, four,five, six, eight, ten or more times greater than the total sum of thedifferences between the x or y coordinates of the first eye compared tothe second eye over the time tested in a healthy control or in areference value based upon one or more healthy controls or based uponthe subject at a time before the disease.

In a nineteenth aspect, the invention provides methods for quantitatingthe extent of disconjugate gaze or strabismus by

-   -   a) Tracking eye movement of both eyes of the subject;    -   b) Analyzing eye movement of both eyes of the subject;    -   c) Comparing the x or y Cartesian coordinates at any time point        for the eye movement of a first eye of the subject to the        respective x or y Cartesian coordinates at the time point for        the eye movement of a second eye of the subject;    -   d) Providing a sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested or providing a sum of the differences in the x or y        coordinates of the first eye compared to the second eye over the        time tested or both; and, optionally    -   e) Providing a total sum of the differences between the x or y        coordinates of the first eye compared to the second eye over the        time tested.

In a twentieth aspect, the invention provides a kit useful fordetecting, screening for or quantitating disconjugate gaze orstrabismus, useful for diagnosing a disease characterized bydisconjugate gaze or strabismus in a subject, useful for detecting,monitoring progression of or screening for a disease or conditioncharacterized by disconjugate gaze or strabismus in a subject or usefulfor quantitating the extent of disconjugate gaze or strabismus,containing a device for tracking eye movement, one or more means foranalyzing eye movement tracking data such as, for instance, an algorithmor computer program, and instructions. Processing eye movementobservations, making measurements of eye movement observations,determining distributions of values measured and performing statisticaltests may all be accomplished using suitable computer software that maybe included in such a kit.

In a twenty first aspect, the invention provides methods for assessingor quantitating structural and non-structural traumatic brain injury by

-   -   a) Tracking eye movement of at least one eye of the subject;    -   b) Analyzing eye movement of at least one eye of the subject;    -   c) Comparing eye movement of at least one eye of the subject to        a normal or mean eye movement; and, optionally    -   d) Calculating a standard deviation or p value for eye movement        of at least one eye of the subject as compared to the normal or        mean eye movement.

In some instances, eye movement of both eyes of the subject are trackedand analyzed. In some instances, the x or y coordinates of eye positionfor one or both eyes of a subject are collected for at least about 100,500, 1,000, 5,000, 10,000, 50,000, 100,000, 200,000 or more eyepositions. In some instances, the eye position is effectively the pupilposition. In some instances the eye movement is tracked for about 30,60, 90, 100, 120, 150, 180, 200, 220, 240, 270, 300, 360 or moreseconds.

The comparing eye movement of at least one eye of the subject to anormal or mean eye movement may feature comparing eye movement of atleast one eye of the subject to the eye movement of the other eye of thesubject or may feature comparing eye movement of at least one eye of thesubject to the eye movement of an eye of one or more other subjects orcontrols. In some instances, the comparing eye movement of at least oneeye of the subject to a normal or mean eye movement may featurecomparing the eye movement of both eyes of the subject to the eyemovement of one or both eyes of one or more other subjects or controls.

In some instances, the method may feature collecting raw x or ycartesian coordinates of pupil position, normalizing the raw x or yCartesian coordinates, and sorting the data by eye.

The method may also feature calculating individual metrics, such as, forinstance, segment mean, segment median, and segment variance. The methodmay also feature calculating specific metrics such as, for example,

L.varYtop=Var(

y _(1,average) _(k=1:5,1) )  (13)

R.varYtop=Var(

y _(2,average) _(k=1:5,1) )  (14)

L.varXrit=Var(

x _(1,average) _(k=1:5,2) )  (15)

R.varXrit=Var(

x _(2,average) _(k=1:5,2) )  (16)

L.varYbot=Var(

y _(1,average) _(k=1:5,3) )  (17)

R.varYbot=Var(

y _(2,average) _(k=1:5,3) )  (18)

L.varXlef=Var(

x _(1,average) _(k=1:5,4) )  (19)

L.varXlef=Var(

x _(2,average) _(k=1:5,4) )  (20)

L.varTotal=Average(Var(

x _(1,average) _(k=1:5) )+Var(

y _(1,average) _(k=1:5) ))  (21)

R.varTotal=Average(Var(

x _(2,average) _(k=1:5) )+Var(

y _(2,average) _(k=1:5) ))  (22)

or segment standard deviation and segment skew such as, for instance,

L.SkewTop=Skew(

y _(1,average) _(k=1:5,1) )  (27)

R.SkewTop=Skew(

y _(2,average) _(k=1:5,1) )  (28)

L.SkewRit=Skew(

x _(1,average) _(k=1:5,2) )  (29)

R.SkewRit=Skew(

x _(2,average) _(k=1:5,2) )  (30)

L.SkewBot=Skew(

y _(1,average) _(k=1:5,3) )  (31)

R.SkewBot=Skew(

y _(2,average) _(k=1:5,3) )  (32)

L.SkewLef=Skew(

x _(1,average) _(k=1:5,4) )  (33)

R.SkewLef=Skew(

x _(2,average) _(k=1:5,4) )  (34)

or segment normalized skew, such as, for instance,

$\begin{matrix}{\mspace{79mu} {{{{SkewNorm}\left( {\overset{\_}{x}}_{j,k,l} \right)} = \frac{{Skew}\left( {\overset{\_}{x}}_{j,k,l} \right)}{\sigma \text{?}}},}} & (35) \\{\mspace{79mu} {{{SkewNorm}\left( {\overset{\_}{y}}_{j,k,l} \right)} = {\frac{{Skew}\left( {\overset{\_}{y}}_{j,k,l} \right)}{\sigma \text{?}}\text{?}}}} & (36) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (43) \\{\mspace{79mu} {{{R.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (44)\end{matrix}$

The method may also feature calculating box height, box width, box area,or box aspect ratio.

Box Height

BoxHeight_(j,k) =

y _(j,k,1) −

y _(j,k,3)  (45)

Box Width

BoxWidth_(j,k) =

x _(j,k,2) −

x _(j,k,4)  (46)

Box Aspect Ratio

$\begin{matrix}{{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}} & (47)\end{matrix}$

Box Area

BoxArea_(j,k)=BoxHeight_(j,k)×BoxWidth_(j,k)  (48)

The method may also feature calculating conjugacy of eye movement orvariance from perfect conjugacy of eye movement, such as, for example,

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYtop}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYrit}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYbot}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYlef}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$

or variance x ratio top/bottom (conjugacy), variance y ratio top/bottom(conjugacy), variance x ratio left/right (conjugacy), or variance yratio left/right (conjugacy).

In some instances, one or more of the L height, L width, L area, LvarXrit, L varXlef, L varTotal, R height, R width, R area, R varYtop, RvarXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, Conj varXbot,Conj varXlef and Conj varYlef may be especially useful for demonstratingor detecting or assessing structural or non-structural traumatic braininjury such as, for instance, a concussion, subconcussion or blastinjury. In some instances, two, three, four, five, six, seven, eight,nine, ten or more metrics may be observed or determined.

A standard deviation or p value of 0.25, 0.3, 0.4, 0.5, 0.75. 0.8, 0.9,1.0, 1.5, 2.0, 2.5 or more may reflect that a subject has structural ornon-structural traumatic brain injury such as, for instance, aconcussion, subconcussion or blast injury. As such, the methodsdescribed herein may be used to detect concussion, subconcussion andblast injury and assess or determine the severity of the same.

In a twenty second aspect, the invention provides methods for diagnosinga disease characterized by or featuring structural and non-structuraltraumatic brain injury in a subject by

-   -   a) Tracking eye movement of at least one eye of the subject;    -   b) Analyzing eye movement of at least one eye of the subject;    -   c) Comparing eye movement of at least one eye of the subject to        a normal or mean eye movement; and, optionally    -   d) Calculating a standard deviation or p value for eye movement        of at least one eye of the subject.

In some instances, eye movement of both eyes of the subject are trackedand analyzed. In some instances, x or y coordinates of eye position forone or both eyes of a subject are collected for at least about 100, 500,1,000, 5,000, 10,000, 50,000, 100,000, 200,000 or more eye positions. Insome instances, the eye position is effectively the pupil position. Insome instances the eye movement is tracked for about 30, 60, 90, 100,120, 150, 180, 200, 220, 240, 270, 300, 360 or more seconds.

The comparing eye movement of at least one eye of the subject to anormal or mean eye movement may feature comparing eye movement of atleast one eye of the subject to the eye movement of the other eye of thesubject or may feature comparing eye movement of at least one eye of thesubject to the eye movement of an eye of one or more other subjects orcontrols. In some instances, the comparing eye movement of at least oneeye of the subject to a normal or mean eye movement may featurecomparing the eye movement of both eyes of the subject to the eyemovement of one or both eyes of one or more other subjects or controls.

In some instances, the method may feature collecting raw x or ycartesian coordinates of pupil position, normalizing the raw x or ycartesian coordinates, and sorting the data by eye.

The method may also feature calculating individual metrics, such as, forinstance, segment mean, segment median, and segment variance. The methodmay also feature calculating specific metrics such as, for example,

L.varYtop=Var(

y _(1,average) _(k=1:5,1) )  (13)

R.varYtop=Var(

y _(2,average) _(k=1:5,1) )  (14)

L.varXrit=Var(

x _(1,average) _(k=1:5,2) )  (15)

R.varXrit=Var(

x _(2,average) _(k=1:5,2) )  (16)

L.varYbot=Var(

y _(1,average) _(k=1:5,3) )  (17)

R.varYbot=Var(

y _(2,average) _(k=1:5,3) )  (18)

L.varXlef=Var(

x _(1,average) _(k=1:5,4) )  (19)

L.varXlef=Var(

x _(2,average) _(k=1:5,4) )  (20)

L.varTotal=Average(Var(

x _(1,average) _(k=1:5) )+Var(

y _(1,average) _(k=1:5) ))  (21)

R.varTotal=Average(Var(

x _(2,average) _(k=1:5) )+Var(

y _(2,average) _(k=1:5) ))  (22)

or segment standard deviation and segment skew such as, for instance,

L.SkewTop=Skew(

y _(1,average) _(k=1:5,1) )  (27)

R.SkewTop=Skew(

y _(2,average) _(k=1:5,1) )  (28)

L.SkewRit=Skew(

x _(1,average) _(k=1:5,2) )  (29)

R.SkewRit=Skew(

x _(2,average) _(k=1:5,2) )  (30)

L.SkewBot=Skew(

y _(1,average) _(k=1:5,3) )  (31)

R.SkewBot=Skew(

y _(2,average) _(k=1:5,3) )  (32)

L.SkewLef=Skew(

x _(1,average) _(k=1:5,4) )  (33)

R.SkewLef=Skew(

x _(2,average) _(k=1:5,4) )  (34)

or segment normalized skew, such as, for instance,

$\begin{matrix}{\mspace{79mu} {{{{SkewNorm}\left( {\overset{\_}{x}}_{j,k,l} \right)} = \frac{{Skew}\left( {\overset{\_}{x}}_{j,k,l} \right)}{\sigma \text{?}}},}} & (35) \\{\mspace{79mu} {{{SkewNorm}\left( {\overset{\_}{y}}_{j,k,l} \right)} = {\frac{{Skew}\left( {\overset{\_}{y}}_{j,k,l} \right)}{\sigma \text{?}}\text{?}}}} & (36) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (43) \\{\mspace{79mu} {{{R.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (44)\end{matrix}$

The method may also feature calculating box height, box width, box area,or box aspect ratio.

Box Height

BoxHeight_(j,k) =

y _(j,k,1) −

y _(j,k,3)  (45)

Box Width

BoxWidth_(j,k) =

x _(j,k,2) −

x _(j,k,4)  (46)

Box Aspect Ratio

$\begin{matrix}{{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}} & (47)\end{matrix}$

Box Area

BoxArea_(j,k)=BoxHeight_(j,k)×BoxWidth_(j,k)  (48)

The method may also feature calculating conjugacy of eye movement orvariance from perfect conjugacy of eye movement, such as, for example,

$\begin{matrix}{{{{Conj}\mspace{14mu} {varXtop}} = \frac{{\sum\left( {\hat{x}}_{1} \right)^{2}} - 0}{\sum{\hat{x}}_{1}}},} & (57) \\{{{{Conj}\mspace{14mu} {varXrit}} = \frac{{\sum\left( {\hat{x}}_{2} \right)^{2}} - 0}{\sum{\hat{x}}_{2}}},} & (58) \\{{{{Conj}\mspace{14mu} {varXbot}} = \frac{{\sum\left( {\hat{x}}_{3} \right)^{2}} - 0}{\sum{\hat{x}}_{3}}},} & (59) \\{{{{Conj}\mspace{14mu} {varXlef}} = \frac{{\sum\left( {\hat{x}}_{4} \right)^{2}} - 0}{\sum{\hat{x}}_{4}}},} & (60) \\{{{{Conj}\mspace{14mu} {varYtop}} = \frac{{\sum\left( {\hat{y}}_{1} \right)^{2}} - 0}{\sum{\hat{y}}_{1}}},} & (61) \\{{{{Conj}\mspace{14mu} {varYrit}} = \frac{{\sum\left( {\hat{y}}_{2} \right)^{2}} - 0}{\sum{\hat{y}}_{2}}},} & (62) \\{{{{Conj}\mspace{14mu} {varYbot}} = \frac{{\sum\left( {\hat{y}}_{3} \right)^{2}} - 0}{\sum{\hat{y}}_{3}}},} & (63) \\{{{{Conj}\mspace{14mu} {varYrit}} = \frac{{\sum\left( {\hat{y}}_{4} \right)^{2}} - 0}{\sum{\hat{y}}_{4}}},} & (64) \\{{{{Conj}\mspace{14mu} {CorrXYtop}} = \frac{\sum{\hat{x}\text{?}}}{{\sum{\hat{x}}_{1}} - 1}},} & (65) \\{{{{Conj}\mspace{14mu} {CorrXYrit}} = \frac{\sum{\hat{x}\text{?}}}{{\sum{\hat{x}}_{2}} - 1}},} & (66) \\{{{{Conj}\mspace{14mu} {CorrXYbot}} = \frac{\sum{\hat{x}\text{?}}}{{\sum{\hat{x}}_{3}} - 1}},} & (67) \\{{{{Conj}\mspace{14mu} {CorrXYlef}} = \frac{\sum{\hat{x}\text{?}}}{{\sum{\hat{x}}_{4}} - 1}}{\text{?}\text{indicates text missing or illegible when filed}}} & (68)\end{matrix}$

or variance x ratio top/bottom (conjugacy), variance y ratio top/bottom(conjugacy), variance x ratio left/right (conjugacy), or variance yratio left/right (conjugacy).

In some instances, one or more of the L height, L width, L area, LvarXrit, L varXlef, L varTotal, R height, R width, R area, R varYtop, RvarXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, Conj varXbot,Conj varXlef and Conj varYlef may be especially useful for demonstratingor detecting or assessing structural or non-structural traumatic braininjury such as, for instance, a concussion, subconcussion or blastinjury. In some instances, two, three, four, five, six, seven, eight,nine, ten or more metrics may be observed or determined.

A standard deviation or p value of 0.25, 0.3, 0.4, 0.5, 0.75. 0.8, 0.9,1.0, 1.5, 2.0, 2.5 or more may reflect that a subject has structural ornon-structural traumatic brain injury such as, for instance, aconcussion, subconcussion or blast injury. As such, the methodsdescribed herein may be used to detect concussion, subconcussion orblast injury and assess or determine the severity of the same. In someinstances the eye movement is tracked for about 30, 60, 90, 100, 120,150, 180, 200, 220, 240, 270, 300, 360 or more seconds.

In a twenty third aspect, the invention provides methods for assessingor quantitating structural and non-structural traumatic brain injury ordiagnosing a disease characterized by or featuring structural andnon-structural traumatic brain injury in a subject by

-   -   a) Tracking eye movement of at least one eye of the subject;    -   b) collecting raw x or y cartesian coordinates of pupil        position;    -   c) normalizing the raw x or y Cartesian coordinates; and    -   d) calculating one or more individual metric.

In some instances, eye movement of both eyes of the subject are trackedand analyzed. In some instances, x or y coordinates of eye position forone or both eyes of a subject are collected for at least about 100, 500,1,000, 5,000, 10,000, 50,000, 100,000, 200,000 or more eye positions. Ininstances where the eye movement of both eyes are tracked, the methodmay additionally feature sorting the data by eye.

The one or more individual metric may be any one of

L.varYtop=Var(

y _(1,average) _(k=1:5,1) )  (13)

R.varYtop=Var(

y _(2,average) _(k=1:5,1) )  (14)

L.varXrit=Var(

x _(1,average) _(k=1:5,2) )  (15)

R.varXrit=Var(

x _(2,average) _(k=1:5,2) )  (16)

L.varYbot=Var(

y _(1,average) _(k=1:5,3) )  (17)

R.varYbot=Var(

y _(2,average) _(k=1:5,3) )  (18)

L.varXlef=Var(

x _(1,average) _(k=1:5,4) )  (19)

L.varXlef=Var(

x _(2,average) _(k=1:5,4) )  (20)

L.varTotal=Average(Var(

x _(1,average) _(k=1:5) )+Var(

y _(1,average) _(k=1:5) ))  (21)

R.varTotal=Average(Var(

x _(2,average) _(k=1:5) )+Var(

y _(2,average) _(k=1:5) ))  (22)

or segment standard deviation and segment skew such as, for instance,

L.SkewTop=Skew(

y _(1,average) _(k=1:5,1) )  (27)

R.SkewTop=Skew(

y _(2,average) _(k=1:5,1) )  (28)

L.SkewRit=Skew(

x _(1,average) _(k=1:5,2) )  (29)

R.SkewRit=Skew(

x _(2,average) _(k=1:5,2) )  (30)

L.SkewBot=Skew(

y _(1,average) _(k=1:5,3) )  (31)

R.SkewBot=Skew(

y _(2,average) _(k=1:5,3) )  (32)

L.SkewLef=Skew(

x _(1,average) _(k=1:5,4) )  (33)

R.SkewLef=Skew(

x _(2,average) _(k=1:5,4) )  (34)

or segment normalized skew, such as, for instance,

$\begin{matrix}{\mspace{79mu} {{{{SkewNorm}\left( {\overset{\_}{x}}_{j,k,l} \right)} = \frac{{Skew}\left( {\overset{\_}{x}}_{j,k,l} \right)}{\sigma \text{?}}},}} & (35) \\{\mspace{79mu} {{{SkewNorm}\left( {\overset{\_}{y}}_{j,k,l} \right)} = {\frac{{Skew}\left( {\overset{\_}{y}}_{j,k,l} \right)}{\sigma \text{?}}\text{?}}}} & (36) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{SkewNorm}\left( {{\overset{\_}{y}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{1,{average}}\mspace{11mu}}\text{?}} \right)}}} & (43) \\{\mspace{79mu} {{{R.{SkewLefNorm}} = {{SkewNorm}\left( {{\overset{\_}{x}}_{{2,{average}}\mspace{11mu}}\text{?}} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (44)\end{matrix}$

The method may also feature calculating box height, box width, box area,or box aspect ratio.

Box Height

BoxHeight_(j,k) =

y _(j,k,1) −

y _(j,k,3)  (45)

Box Width

BoxWidth_(j,k) =

x _(j,k,2) −

x _(j,k,4)  (46)

Box Aspect Ratio

$\begin{matrix}{{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}} & (47)\end{matrix}$

Box Area

BoxArea_(j,k)=BoxHeight_(j,k)×BoxWidth_(j,k)  (48)

The method may also feature calculating conjugacy of eye movement orvariance from perfect conjugacy of eye movement, such as, for example,

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYtop}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYrit}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYbot}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {CorrXYlef}} = \frac{\sum\; \text{?}}{\sum\; \text{?}}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$

or variance x ratio top/bottom (conjugacy), variance y ratio top/bottom(conjugacy), variance x ratio left/right (conjugacy), or variance yratio left/right (conjugacy).

In some instances, one or more of the L height, L width, L area, LvarXrit, L varXlef, L varTotal, R height, R width, R area, R varYtop, RvarXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, Conj varXbot,Conj varXlef and Conj varYlef may be especially useful for demonstratingor detecting or assessing structural or non-structural traumatic braininjury such as, for instance, a concussion, subconcussion or blastinjury. In some instances, two, three, four, five, six, seven, eight,nine, ten or more metrics may be observed or determined.

A standard deviation or p value of 0.25, 0.3, 0.4, 0.5, 0.75. 0.8, 0.9,1.0, 1.5, 2.0, 2.5 or more may reflect that a subject has structural ornon-structural traumatic brain injury such as, for instance, aconcussion, subconcussion or blast injury. As such, the methodsdescribed herein may be used to detect concussion and assess ordetermine the severity of the same.

In a twenty fourth aspect, the invention provides a kit useful fordetecting, screening for or quantitating structural and non-structuraltraumatic brain injury in a subject, containing a device for trackingeye movement, one or more means for analyzing eye movement tracking datasuch as, for instance, an algorithm or computer program, andinstructions. Processing eye movement observations, making measurementsof eye movement observations, determining distributions of valuesmeasured and performing statistical tests may all be accomplished usingsuitable computer software that may be included in such a kit.

In a twenty fifth aspect, the invention provides a computer system. Thecomputer system or computing device 1000 can be used to implement adevice that includes the processor 106 and the display 108, the eyemovement/gaze tracker component 104, etc. The computing system 1000includes a bus 1005 or other communication component for communicatinginformation and a processor 1010 or processing circuit coupled to thebus 1005 for processing information. The computing system 1000 can alsoinclude one or more processors 1010 or processing circuits coupled tothe bus for processing information. The computing system 1000 alsoincludes main memory 1015, such as a random access memory (RAM) or otherdynamic storage device, coupled to the bus 1005 for storing information,and instructions to be executed by the processor 1010. Main memory 1015can also be used for storing position information, temporary variables,or other intermediate information during execution of instructions bythe processor 1010. The computing system 1000 may further include a readonly memory (ROM) 1010 or other static storage device coupled to the bus1005 for storing static information and instructions for the processor1010. A storage device 1025, such as a solid state device, magnetic diskor optical disk, is coupled to the bus 1005 for persistently storinginformation and instructions.

The computing system 1000 may be coupled via the bus 1005 to a display1035, such as a liquid crystal display, or active matrix display, fordisplaying information to a user. An input device 1030, such as akeyboard including alphanumeric and other keys, may be coupled to thebus 1005 for communicating information and command selections to theprocessor 1010. In another implementation, the input device 1030 has atouch screen display 1035. The input device 1030 can include a cursorcontrol, such as a mouse, a trackball, or cursor direction keys, forcommunicating direction information and command selections to theprocessor 1010 and for controlling cursor movement on the display 1035.

According to various implementations, the processes described herein canbe implemented by the computing system 1000 in response to the processor1010 executing an arrangement of instructions contained in main memory1015. Such instructions can be read into main memory 1015 from anothercomputer-readable medium, such as the storage device 1025. Execution ofthe arrangement of instructions contained in main memory 1015 causes thecomputing system 1000 to perform the illustrative processes describedherein. One or more processors in a multi-processing arrangement mayalso be employed to execute the instructions contained in main memory1015. In alternative implementations, hard-wired circuitry may be usedin place of or in combination with software instructions to effectillustrative implementations. Thus, implementations are not limited toany specific combination of hardware circuitry and software.

Eye Movement Tracking Device

According to the methods described, tracking eye movement may beperformed using any suitable device such as, for example, an Eyelink®1000 binocular eye tracker (500 Hz sampling, SR Research). The eyetracking movement samples may be obtained at any suitable frequency,such as for instance, 10 Hz to 10,000 Hz or more. The subject may bepositioned an appropriate distance from the device, such as, forexample, 10, 20, 30, 40, 50, 55, 60, 70, 80, 90 cm or more, or even ameter or more from the device screen. In some instances, the subject'shead may be stabilized, such as, for instance by using a chinrest orsimilar stabilizing mechanism. The subject may be seated or reclining.Preferably, the presentation monitor of the device is adjusted so as tosubstantially match the subject's gaze direction. The tracking eyemovement may be performed for a total of, for example, 30, 60, 90, 120,150, 180, 200, 220, 240, 270, 300, 330, 360, 400, 450, 500 seconds ormore, or for 5, 10, 15, 20, 25, 30, 45, 60, or 90 minutes or more. Assuch, according to the methods provided, 1,000, 5, 000, 10,000, 20,000,25, 000, 50,000, 75,000, 100,000, 150,000, 200,000, 250,000, 300,000 ormore samples of eye position may be obtained. Similarly, the trackingeye movement may be performed using a video oculography device, such as,for instance, goggles, or using a web-cam based tracking system.

According to the methods described, analyzing eye movement may beperformed by any suitable means. In some instances, a stimulus and ananalysis stream are provided that allows interpreting raw eye positiondata. In some instances, an algorithm may be provided for looking atpupil position directly thereby yielding information about ocularmotility. Preferably, a device is adapted into a novel mobile systemthat may analyze eye movement close in time or substantially concurrentto the eye movement itself.

Tracking Eye Movement in Response to a Moving or Visual Stimulus

According to the methods described, eye movement may be tracked inresponse to a visual stimulus. In some instances, the visual stimulusmay be, for instance, a video such as a music video that may move, forinstance clockwise, along the outer edge, of a computer monitor. In someinstances, such a video may be provided starting at the upper or lower,left or right hand corners, of a screen. The visual stimulus such as avideo, e.g. a music video, may be provided in a substantially squareaperture with an area of approximately 10, 12, 14, 16, 18, 20, 25, ordegrees, for example, approximately 1/10, ⅛, ⅙, ⅕, ¼, ⅓, ½ of the sizeof the screen or so. The visual stimulus, such as, for example a musicvideo, may play substantially continuously during the eye movementtracking, and it may in some instances move across the screen at arelatively or substantially constant speed. For instance, such a visualstimulus, for instance, a music video may cover each edge of a monitorin about 2, 5, 10, 15, 20, 30, 45 or 60 seconds or so. Therefore, insome instances, a full cycle may take, for instance, 10, 20, 30, 40, 50,60, 75, 100, 120, 150, 180 seconds or so. Multiple cycles of such avisual stimulus, for instance a music video may be played, for instance,one, two, three, four, five, six, seven, eight, nine, ten, twelve,fifteen, twenty or more full cycles. As such, the visual stimulus may beprovided, the eye movement may be tracked, in effect, in some instancesthe video may be played for a total of, for example, 30, 60, 90, 120,150, 180, 200, 220, 240, 270, 300, 330, 360, 400, 450, 500 seconds ormore. In instances where the visual stimulus is in the form of a video,a countdown video may be played in the starting position for, forinstance, 5, 10, 15, 20, 25, or 30 seconds or more before beginning thevisual stimulus, e.g. video, to provide subjects sufficient time toorient to the visual stimulus. Likewise, the visual stimulus, forinstance a video, may be continued for an addition 2, 5, 10, 15, 20, 30,45 or 60 seconds or so after the eye movement tracking is performed toreduce or substantially avoid boundary effects. The same result could beobtained by having the visual stimulus moving over any distance xrelative to any amount of time t. The ideal stimulus would move howeverin both the x and y Cartesian planes to optimize the assessmentcapability of the method.

According to the methods described, comparing eye movement of a firsteye of the subject to eye movement of a second eye of the subject, maybe performed by analyzing data. Data from the tracking eye movement mayprovide an indication of whether an individual subject's gaze isconjugate (eyes are moving together) versus disconjugate. Comparing eyemovement of a first eye of the subject to eye movement of a second eyeof the subject may feature generating scatterplots. Comparing eyemovement of a first eye of the subject to eye movement of a second eyeof the subject, may feature plotting the horizontal eye position alongone axis and vertical eye position along an orthogonal axis. Suchcomparing eye movement of the subject to a control, or comparing eyemovement of a first eye of the subject to eye movement of a second eyeof the subject, may feature generating, plotting pairs of (x,y) values,for instance, 50,000, 100,000 or more pairs of values (x,y). Such pairsof values (x,y) may be plotted representing, for instance, the twocomponents of the instantaneous angle of pupil reflection (horizontal,vertical) over a period of time, for instance, 100 or 200 seconds ormore.

As such, comparing eye movement of a first eye of the subject to eyemovement of a second eye of the subject, may feature generating figuressubstantially resembling boxes that reflect the trajectory traveled bythe visual stimulation, such as when it moves across a screen. Inhealthy controls, these figures substantially resembling boxes may looklike, for instance, substantially equilateral rectangles or squares,reflecting the trajectory traveled by the visual stimulus across ascreen. In instances of neurological damage or increased intracranialpressure, such figures may not substantially resemble a box, a rectangleor a square. In fact, in some instances, the cranial nerve havingreduced or impaired function or conduction may be identified. In someinstances, the figures generated that reflect the trajectory traveled bythe visual stimulation may demonstrate abnormal distribution of orabsence of normal plotting pairs in particular areas. Increasedvariability along the y-axis may for example reflect cranial nerve IIdysfunction. Decreased variability along the y-axis, or decreased heightto width ratio may reflect CN III dysfunction. Increased height to widthratio may reflect CN IV or VI dysfunction. The height of the box may bemathematically determined by assessing the position of the pupil as thevideo traverses the top and bottom of the presented visual stimulus.This “actual” height may be different from the perceived heightmathematically, since the perceived height can represent aberrantpupillary motion due to the patient's ocular motility dysfunction. Theintegrity of the box walls may also be indicative of other types ofdysfunction. Both cranial nerve palsies and mass effect may causedefects in box trajectory. Supratentorial mass lesions and CN IIIdefects may impact the top and/or bottom of the box. Infratentorial masslesions or CN VI palsies may impact the sides of the box. For instance,in the case of the left eye, the upper left quadrant of the figure mayreflect activity, function or conduction of cranial nerves III and VI,the lower left quadrant of the figure may reflect activity, function orconduction of cranial nerves III and IV, while the upper right quadrantand the lower right quadrants may reflect activity, function orconduction of cranial nerve III. In the case of the right eye, the upperand lower left quadrants of the figure may reflect activity, function orconduction of cranial nerve III, the lower right quadrant of the figuremay reflect activity, function or conduction of cranial nerve III, whilethe upper right quadrant and the lower right quadrant may reflectactivity, function or conduction of cranial nerves IV and VI.

Comparing eye movement of a first eye of the subject to eye movement ofa second eye of the subject, may feature determining the distribution ofcertain measurements in the control population and comparing the subjectwith these control distributions. In such instances, visual stimulustrajectory may be divided into four time components, for instance, two,three, four, five, six or more repetitions of the first few, forinstance, 2, 5, 10, 15, 20 or so seconds of each rotation cycle. In suchinstances, comparing eye movement of the subject to a control mayfeature evaluating such variables as the relative variance in each arm,and the relative integrity of each arm.

Comparing eye movement of the subject to a control, or comparing eyemovement of a first eye of the subject to eye movement of a second eyeof the subject, may also feature measuring the integrity of eachsubject's values. In instances featuring generating figuressubstantially resembling boxes that reflect the trajectory traveled bythe visual stimulation, such as when it moves across a screen, the sidesor arms of the figures (e.g. the top of the box and the bottom of thebox) may be z-scored using the mean and standard deviation calculatedfrom the control population. The resulting score may indicate howdifferent the subject's values are compared with the control values,such as, for instance, in units of standard deviations.

According to the methods described, identifying the subject as havingeye movement significantly different from the control, or identifyingthe subject as having eye movement of a first eye that is significantlydifferent from eye movement of a second eye, may be performed using az-score. Because 95% of all values in a normal distribution lie withintwo standard deviations of the mean, a z-score of 2 may be used as asignificance threshold. Subjects with z-scores above, for instance, 2 ineither or both, or 1, 2, 3, or 4 sides or arms of the figures may bejudged to have significant disturbances of ocular motility.

Identifying the subject as having eye movement significantly differentfrom the control, or identifying the subject as having eye movement of afirst eye that is significantly different from eye movement of a secondeye, may feature determining relative variance. In some instances,multiple such as 1,000, 2,000, 3,000, 5,000, 10,000, 20,000 or morepoint distributions may be generated by, for instance, taking multiplesamples from a multiple number of values randomly chosen withreplacement from the multiple control values. For each subject, therelative variance in either or both, or 1, 2, 3, or 4 sides or arms ofthe figures may be compared respectively with the corresponding controldistribution, and the percent of the control distribution with variancebelow that of the test value may be determined. A p-value of 0.05 awidely accepted measure of statistical significance corresponds to 95%of control values falling below the test value. In such instances,subjects with variance higher than 95% of the values in the controldistributions may be determined to have significant disturbances ofocular motility. The video may also move in other trajectories notresembling a rectangle, such as a triangle, circle or linear ornonlinear trajectories. As long as the trajectories can be resolved intovectors along Cartesian coordinates (horizontal vertical or x,y) thesame principles apply. In short, any trajectory (e.g. any shape, orline, or curve, etc.) studied over time may provide information aboutCentral Nervous System function or dysfunction.

Comparing the movement of one eye of a subject to the other eye of asubject may be performed by comparing the x or y Cartesian coordinatesat any time point t, for example, by subtracting the x coordinate of theleft eye from the x coordinate of the right eye or vice versa, or bysubtracting the y coordinate of the left eye from the y coordinate ofthe right eye or vice versa. The sums of the differences between all ofthe x coordinates over the time tested informs regarding horizontalmovement of the pupil. The sums of the differences in y coordinates overtime informs regarding vertical movement of the pupil. The total sum ofthe differences between both x and y coordinates over the time testedmay be totaled to obtain a measure of total disconjugacy of gaze, whichis a surrogate marker for central nervous system integrity. In such away, it is possible to quantitate the extent of central nervous system(CNS) integrity by quantitating the extent of disconjugate gaze. Acomparative study of horizontal, vertical, and total disconjugacy usingdifferent kinds of visual stimuli demonstrated that horizontal axisconjugacy was greater than or equal to vertical axis conjugacy. As such,either x or y conjugacy may be used singly to assess the extent ofdisconjugate gaze.

Eye Movement Tracking without a Moving or Visual Stimulus

Eye movement may also be tracked without using a moving stimulus. It ispossible to assess conjugacy without having the stimulus move at all,but by assessing the x or y coordinates over times during naturalisticviewing. For example, eye movement may be tracked during televisionwatching or live viewing of an environment without a specific viewingapparatus such as a monitor or screen.

According to the methods described, comparing the x or y Cartesiancoordinates at any time point for the eye movement of a first eye of thesubject to the respective x or y Cartesian coordinates at any time pointfor the eye movement of a second eye of the subject, may be performed byanalyzing data. Data from the tracking eye movement may provide anindication of whether an individual subject's gaze is conjugate (eyesare moving together) versus disconjugate. Comparing the x or y Cartesiancoordinates at any time point for the eye movement of a first eye of thesubject to the respective x or y Cartesian coordinates at any time pointfor the eye movement of a second eye of the subject, may featuregenerating scatterplots. Comparing the x or y Cartesian coordinates atany time point for the eye movement of a first eye of the subject to therespective x or y Cartesian coordinates at any time point for the eyemovement of a second eye of the subject, may feature plotting thedifference between the horizontal eye positions along one axis and timealong an orthogonal axis, or the difference between the vertical eyepositions along one axis and time along an orthogonal axis. Suchcomparing the x or y Cartesian coordinates at any time point for the eyemovement of a first eye of the subject to the respective x or yCartesian coordinates at any time point for the eye movement of a secondeye of the subject, may feature generating, plotting pairs of (x or y)values, for instance, 25,000, 50,000, 75,000, 100,000, 150,000 or morepairs of values (x or y). Such pairs of values (x or y) may be plottedrepresenting, for instance, the two components of the instantaneousangle of pupil reflection (horizontal, vertical) over a period of time,for instance, 100 or 200 or 250 or 300 seconds or more.

As such, comparing the x or y Cartesian coordinates at any time pointfor the eye movement of a first eye of the subject to the respective xor y Cartesian coordinates at the time point for the eye movement of asecond eye of the subject, may allow generating plots assessingconjugacy of eye movements over time.

Comparing the x or y Cartesian coordinates at any time point for the eyemovement of a first eye of the subject to the respective x or yCartesian coordinates at the time point for the eye movement of a secondeye of the subject, may feature determining the distribution of certainmeasurements in the control population and comparing the subject withthese control distributions. In such instances, visual stimulustrajectory may be divided into four time components, for instance, two,three, four, five, six or more repetitions of the first few, forinstance, 2, 5, 10, 15, 20 or so seconds of each rotation cycle. In suchinstances, comparing the x or y Cartesian coordinates at any time pointfor the eye movement of a first eye of the subject to the respective xor y Cartesian coordinates at any time point for the eye movement of asecond eye of the subject may feature evaluating such variables as therelative variance in each arm, and the relative integrity of each arm.

Comparing the x or y Cartesian coordinates at any time point for the eyemovement of a first eye of the subject to the respective x or yCartesian coordinates at the time point for the eye movement of a secondeye of the subject may be performed by comparing the x or y Cartesiancoordinates at any time point t, for example, by subtracting the xcoordinate of the left eye from the x coordinate of the right eye orvice versa, or by subtracting the y coordinate of the left eye from they coordinate of the right eye or vice versa. The sums of the differencesbetween all of the x coordinates over the time tested informs regardinghorizontal movement of the pupil. The sums of the differences in ycoordinates over time informs regarding vertical movement of the pupil.The total sum of the differences between both x and y coordinates overthe time tested may be totaled to obtain a measure of total disconjugacyof gaze, which may be a surrogate marker for central nervous systemintegrity. In such a way, it is possible to quantitate the extent ofcentral nervous system (CNS) integrity by quantitating the extent ofdisconjugate gaze. A comparative study of horizontal, vertical, andtotal disconjugacy using different kinds of visual stimuli demonstratedthat horizontal axis conjugacy was greater than or equal to verticalaxis conjugacy. As such, either x or y conjugacy may be used singly toassess the extent of disconjugate gaze.

Providing a sum of the differences between all of the x coordinates ofthe first eye compared to the second eye over the time tested orproviding a sum of the differences in y

coordinates of the first eye compared to the second eye over the timetested or both may be performed subsequent to comparing the x or yCartesian coordinates at the time point t. For example, by subtractingthe x coordinate of the left eye from the x coordinate of the right eyeor vice versa. Also, by subtracting the y coordinate of the left eyefrom the y coordinate of the right eye or vice versa. The sums of thedifferences between all of the x coordinates over the time testedinforms regarding horizontal movement of the pupil. The sums of thedifferences in y coordinates over time informs regarding verticalmovement of the pupil. The total sum of the differences between both xand y coordinates over the time tested can be summed to obtain a measureof total disconjugacy of gaze, or as an average of five eyeboxtrajectory cycles formulaically represented as follows:

${X_{{Avg},{ik}} = \frac{\sum\limits_{j = 1}^{5}\; X_{ijk}}{5}},{{{for}\mspace{14mu} {all}\mspace{14mu} i} = {1\text{:}N}},{k = {1\text{:}2}},$

where X_(ijk) refers to the x-coordinate of the pupil, and k refers tothe left or right eye of a subject. In cases where a subject's data wasmissing at any given time point in the five cycles, the denominator ofthe equation was the number of cycles where the data was present. Thedifference in the x or y position, for the left and right eye, may thenbe computed. This vector of difference may then be plotted graphicallyfor purposes of assessment and interpretation. To have a single metricexpressing the level of pupil disconjugation, a variance of the data maybe computed with respect to an expected mean of zero. This issignificant because the code assumes that a healthy subject has zerovertical or horizontal pupil position difference between each eye. Thevariance for either horizontal (x) or vertical (substitute y for x)movement may be computed as follows:

${Var}_{x} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}\; \left( {\left\lbrack {(X\rbrack_{{Avg},{i\; 1}} - X_{{Avg},{i\; 2}}} \right) - 0} \right)^{2}}}$

Providing a total sum of the differences between both x and ycoordinates of the first eye compared to the second eye over the timetested may be performed by calculating the total variance in both thehorizontal and vertical planes between the first and the second eyes.The total variance may be computed as follows:

Var_(Tot)−Var_(x)+Var_(y).

In some instances, the Var_(x) or the Var_(y) or both, calculated asdescribed herein, may be 0.05, 0.07, 0.1, 0.15, 0.20, 0.25, 0.30, 0.40,0.50, 0.60, 0.75, 0.90, 1.0, 1.10, 1.25, 1.50, 1.75, or 2.0 or more.Similarly, in some instances, the Var_(Tot) calculated as describedherein, may be 0.1, 0.15, 0.20, 0.25, 0.30, 0.40, 0.50, 0.60, 0.75,0.90, 1.0, 1.10, 1.25, 1.50, 1.75, 2.0, 2.50, 3.0 or 4.0 or more, insubjects having a neurological disease or condition characterized by orfeaturing disconjugacy of gaze or strabismus.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 (A and B) demonstrates that as the aperture containing a videomoves in a rectangular pattern, different nerves move the pupils. FIG.1A demonstrates movement of the left eye, and FIG. 1B demonstratesmovement of the right eye. Cranial nerve III moves the pupil up anddown. Cranial nerve VI moves it laterally. This data was obtained on amonocular eye tracker with sequential tracking of each eye. The videogoes around five times with each tracking recorded in a separate color(red, green, cyan, magenta, blue).

FIGS. 2 A and B represent the eye-box trajectory of a normal subjecttracked binocularly (FIG. 2A, left eye; FIG. 2B right eye). Note thatthe eyes appear to be moving relatively the same, with some differences.FIGS. 2 C and D are time-course representations (FIG. 2C, left eye; FIG.2D right eye), in which the x-axis is the Cartesian coordinate of theeye position and the y-axis is time.

FIG. 3 demonstrates the binocular eye tracking of a subject whounderwent surgical evacuation of an acute on chronic subdural hematoma.FIGS. 3A and 3B represent eye-box trajectories (FIG. 3A, left eye; FIG.3B right eye). FIGS. 3C and 3D are time-course representations (FIG. 3C,left eye; FIG. 3D right eye), in which the x-axis is the Cartesiancoordinate of position and the y-axis is time. The eyes are not asconjugate as the subject in FIG. 2.

FIG. 4 demonstrates the binocular eye movement tracking of a subjectwith a mild Bird nerve palsy recruited from the ophthalmology clinic.The subject reported increased lacrimation but no diplopia. FIGS. 4A and4B represent eye-box trajectories (FIG. 4A, left eye; FIG. 4B righteye). FIGS. 4C and 4D are time-course representations (FIG. 4C, lefteye; FIG. 4D right eye), in which the x-axis is the Cartesian coordinateof the eye position and the y-axis is time. The eyes are not asconjugate as the subject in FIG. 2 in the x-plane but are completelydisconjugate in the y-plane. The eye tracking anomaly appearscontralateral to the ocular pathology.

FIG. 5 demonstrates the binocular tracking of a subject with concussion.The subject experienced a witnessed fall with blunt head trauma whileattending a clinic in the hospital. FIGS. 5A and 5B represent eye-boxtrajectories (FIG. 5A, left eye; FIG. 5B right eye). FIGS. 5C and 5D aretime-course representations (FIG. 5C, left eye; FIG. 5D right eye), inwhich the x-axis is the Cartesian coordinate of the eye position and they-axis is time. The subject was unable to watch much of the video, butfor the little that he did watch, his y, more so than his x, wasdisconjugate. His head computed tomography scan did not show anyevidence of acute structural injury. The eye tracking is thus showingconcussion (radiographically silent) brain injury.

FIG. 6 demonstrates that binocular eye movement tracking may be usefulto quantitate the extent of physiologic brain injury. The eye boxtrajectory from a normal subject shows highly conjugate gaze (FIG. 6A,x-plane; FIG. 6B y-plane). A subject with third nerve palsy shows onlydiconjugacy in the y-plane (FIG. 6E, x-plane; FIG. 6F y-plane). Asubject with structural brain injury has disconjugacy in both x and yplanes (FIG. 6G, x-plane; FIG. 6H y-plane), as does a concussion subject(FIG. 6C, x-plane; FIG. 6D y-plane).

FIG. 7 represents total conjugacy versus age. Normal subjectsdemonstrated conjugate eye movement that was not impacted by age. Alinear regression t-test was used to determine whether the slope of therelationship between total variance and age yielded a regression linestatistically significantly different from 0. The test resulted in at-statistic of −0.523 and a p-value of 0.6017 showing that the slope ofthe regression line was not statistically significantly different from0. Thus in our subject population ranging in age from 7 to 75, there wasno change in conjugacy of eye movements with age.

FIG. 8 represents male versus female conjugacy of eye movements. Normalsubjects demonstrated conjugate eye movement that was not impacted bygender. A Welch Two Sample t-test with 68.49 degrees of freedom resultedin a t-statistic of 0.6734 and a p-value of 0.5029 showing that thedifference in the means was not statistically significantly differentfrom 0.

FIG. 9 represents X (horizontal) versus Y (vertical) conjugacy. Normalsubjects demonstrated horizontal eye movement that was statisticallyhighly significantly more conjugate than vertical eye movement. A pairedt-test was used to determine if the mean of the subject-paireddifferences between the total x-variance and total y-variance wasstatistically significantly different from 0. With 124 degrees offreedom, the test resulted in a t-statistic of −3.0263 and a p-value of0.003011 showing that the mean of the subject-paired differences wasstatistically highly significantly different from 0. Specifically, itwas shown that for a particular subject, x-variance is statisticallysignificantly less than y-variance.

FIG. 10 demonstrates the test-retest reliability of a stationary tostationary tracker. Subjects (n=27) demonstrated high test-retestreliability between two separate eyetracking sessions on the stationarytracker. A paired t-test was used to determine if the mean of thesubject-paired differences between the total variances for two separateeyetracking sessions was statistically significantly different from 0.With 26 degrees of freedom, the test resulted in a t-statistic of 1.2778and a p-value of 0.2126 showing that the mean of the subject-paireddifferences was not statistically significantly different from 0.

FIG. 11 demonstrates the test retest reliability of a stationary toportable tracker. Subjects (n=24) demonstrated high test-retestreliability between separate eyetracking sessions on the stationarytracker and the portable tracker (FIG. 10). A paired t-test with 23degrees of freedom (n=24), resulted in a t-statistic of 1.3661 and ap-value of 0.1851 showing that the mean of the subject-paireddifferences was not statistically significantly different from 0.

FIG. 12 provides the eye movement tracking trajectories of subjects withcranial nerve IV, III and VI palsies.

FIG. 13 is a block diagram of a computer system in accordance with anillustrative implementation.

FIG. 14 is a schematic diagram showing a configuration of how asubject's eye movements are measured, analyzed and displayed by such acomputer system.

FIG. 15 provides a representation of the binocular eye movement trackingof a normal subject. A, B provide box plots of eye movement in responseto a moving stimulus. The aspect ratio for each eye is provided. C, Dprovide graphic representation of the eye movement tracking for each eyeover time. E, F provide graphical representation of the variance inx-axis movement between the left and right eye and the variance iny-axis movement between the left and right eye. Total variance of x andy coordinates of eye movement over time is provided.

FIG. 16 provides a representation of the eye movement of a patient withconjunctivitis due to a blocked lacrimal duct. A, B provide box plots ofeye movement. The aspect ratio for each eye is provided. C, D providegraphic representation of the eye movement tracking for each eye overtime. E, F provide graphical representation of the variance in x-axismovement between the left and right eye and the variance in y-axismovement between the left and right eye. Total variance of x and ycoordinates of eye movement over time is provided. The same informationis provided after resolution of symptoms. G, H provide box plots of eyemovement. The aspect ratio for each eye is provided. I, J providegraphic representation of the eye movement tracking for each eye overtime. K, L provide graphical representation of the variance in x-axismovement between the left and right eye and the variance in y-axismovement between the left and right eye. Total variance of x and ycoordinates of eye movement over time is provided. Total variance(disconjugacy) is markedly improved after resolution of symptoms.

FIG. 17 provides a representation of the eye movement of a 9 year oldpatient with a history of lymphoma and exotrophic strabismus. A, Bprovide box plots of eye movement. The aspect ratio for each eye isprovided. C, D provide graphic representation of the eye movementtracking for each eye over time. E, F provide graphical representationof the variance in x-axis movement between the left and right eye andthe variance in y-axis movement between the left and right eye. Totalvariance of x and y coordinates of eye movement over time is provided.

FIG. 18 provides a representation of the eye movement of subjects withcranial nerve palsies. A, B provide box plots of eye movement in apatient having a cranial nerve IV palsy. The aspect ratio for each eyeis provided. C, D provide graphical representation of the variance inx-axis movement between the left and right eye and the variance iny-axis movement between the left and right eye. Total variance of x andy coordinates of eye movement over time is provided. E, F provide boxplots of eye movement in a patient having a diabetic cranial nerve IIIpalsy. The aspect ratio for each eye is provided. G, H provide graphicalrepresentation of variance over time. I, J provide box plots of eyemovement in a patient having a post-surgical cranial nerve VI palsy. Theaspect ratio for each eye is provided. K, L provide graphicalrepresentation of variance over time.

FIG. 19 provides a representation of the eye movement of a 35 year oldpatient with a ruptured cerebral aneurysm resulting in subarachnoidhemorrhage. A, B provide box plots of eye movement. The aspect ratio foreach eye is provided. C, D provide graphic representation of the eyemovement tracking for each eye over time. E, F provide graphicalrepresentation of variance over time. The total variance of x and ycoordinates is provided. G, H provide box plots of eye movement in thepatient 6 days later, after embolization of the aneurysm. The aspectratio for each eye is provided. I, J provide graphic representation ofthe eye movement tracking for each eye over time. K, L provide graphicalrepresentation of the variance in x-axis movement between the left andright eye and the variance in y-axis movement between the left and righteye. Total variance of x and y coordinates of eye movement over time isprovided.

FIG. 20 provides a representation of the eye movement of a brain injuredsubject. A, B provide box plots of eye movement. The aspect ratio foreach eye is provided. C, D provide graphic representation of the eyemovement tracking for each eye over time. E, F provide graphicalrepresentation of the variance in x-axis movement between the left andright eye and the variance in y-axis movement between the left and righteye. Total variance of x and y coordinates of eye movement over time isprovided.

FIG. 21 provides a representation of the eye movement of a subjectsuffering a concussion. A, B provide box plots of eye movement. Theaspect ratio for each eye is provided. C, D provide graphicrepresentation of the eye movement tracking for each eye over time. E, Fprovide graphical representation of variance over time. The totalvariance of x and y coordinates is provided.

FIG. 22 provides a representation of the eye movement of a subjectsuffering a concussion. A, B provide box plots of eye movement on theday of the fall resulting in the concussion. The aspect ratio for eacheye is provided. C, D provide graphic representation of the eye movementtracking for each eye over time. Disconjugacy is calculated orquantified. E, F provide box plots of eye movement ten days after thefall resulting in the concussion. The aspect ratio for each eye isprovided. G, H provide graphical representation of the variance inx-axis movement between the left and right eye and the variance iny-axis movement between the left and right eye. Total variance of x andy coordinates of eye movement over time is provided. Disconjugacy iscalculated or quantified. I, J provide box plots of eye movement threeweeks after the fall resulting in the concussion. The aspect ratio foreach eye is provided. K, L provide graphic representation of the eyemovement tracking for each eye over time. Disconjugacy is calculated orquantified.

FIG. 23 provides a representation of the disconjugate gaze in a subjectsuffering a severed cranial nerve III. A-N provide box plots of eyemovement tracking (left and right eyes). The aspect ratio for each eyeis provided. O, P, Q provide graphic representation of the eye movementtracking for each eye over time demonstrating the variance in x-axismovement between the left and right eye and the variance in y-axismovement between the left and right eye.

FIG. 24 provides a representation of the conjugate gaze in a normalsubject while watching television. A-N provide box plots of eye movementtracking (left and right eyes). The aspect ratio for each eye isprovided. O, P, Q provide graphic representation of the eye movementtracking for each eye over time demonstrating the variance in x-axismovement between the left and right eye and the variance in y-axismovement between the left and right eye. Conjugacy is calculated orquantified at 0.0169.

FIG. 25 provides a representation of the disconjugate gaze in a subjectwith a surgically severed cranial nerve III. A-N provide box plots ofeye movement tracking (left and right eyes). The aspect ratio for eacheye is provided. O, P, Q provide graphic representation of the eyemovement tracking for each eye over time demonstrating the variance inx-axis movement between the left and right eye and the variance iny-axis movement between the left and right eye. Disconjugacy iscalculated or quantified at 2.2711.

FIG. 26 represents findings from a 38 year old right-handed malerecruited from the emergency room after being hit by a car while ridinghis bicycle. The patient was brought in with a backboard and C-collar,intoxicated with reported loss of consciousness and normal vitals butintermittent confusion with retrograde amnesia. On physical examinationhe was alert and oriented ×3, had a right eye hematoma and a posteriorvertex soft tissue hematoma. He had active bleeding over a 5 cm verticallaceration overlying the left maxilla. A. Head CT findings includebilateral parafalcine posterior vertex subdural hematomas measuring upto 8 mm in thickness. There were multiple punctuate-subcentimeterbifrontal contusions, right greater than left. There was a 4 mm leftparafalcine subdural hematoma. He had no significant ophthalmic historyfollowing his last optometric visit 10 years prior. No other major bodyinjuries. Quantitative serum alcohol level was 130 mg/dl. Medicationsadministered up to 24 hours prior to recruitment included acetaminophen325 mg, bacitracin, moxifloxacin hydrochloride. B. Represents eyemovement tracking box plots 2 days after triage. The patient waspositive for 12/22 symptoms according to SCAT3 with a severity score of45/132 and GCS score of 13/15. Total SAC score of 17/30. C. Representeye movement tracking box plots 13 days after triage. The patient waspositive for 10/22 symptoms according to SCAT3 with a severity score of27/132 and GCS score of 15/15. Total SAC score of 24/30. Medicationsadministered up to 24 hours prior to eye tracking included ibuprofen.

FIG. 27 represents findings from a 37 year old right-handed female. Thepatient fell 2 weeks prior to seeking medical care. She denied loss ofconsciousness at the time. After taking aspirin, she developed wordfinding difficulty 4 days prior to admission. She presented to theemergency room where her examination was otherwise non-focal. A. Thehead CT showed a mixed attenuation predominantly hyperdense subduralfluid collection over the left cerebral convexity measuring up to 1.7 cmin thickness with associated mass effect upon the left lateral ventricleand 7 mm left to right midline shift of the septum pellucidum. Thepatient underwent craniotomy and was recruited for the study from NSICUon the third postoperative day. She denied word finding difficulty andwas neurologically non-focal at the time of recruitment and reported noophthalmic history. Medications administered up to 24 hours prior torecruitment included Keppra, Ancef, Nexium, Heparin, Acetaminophen,Zofran. There were no drugs or alcohol reported for the past 24 hours.B. Represents eye movement tracking box plots 3 days post operativelyand 17 days post injury patient. The patient was positive for 6/22symptoms according to SCAT3 with a severity score of 17/132 and GCSscore of 15/15. Total SAC score of 18/30. C. Represents eye movementtracking box plots at 35 days post surgery and 49 days post injury. Thepatient was positive for 13/22 symptoms according to SCAT3 with aseverity score of 32/132 and GCS score of 15/15. Total SAC score of27/30. No medications, drugs or alcohol 24 hours prior.

FIG. 28 represents findings from a 22 year old right-handed malerecruited from the emergency room who was participating in a skateboardcompetition and experienced a fall from 10-15 feet landing on hisunhelmeted head. He lost consciousness for approximately 30 minutes andthen was agitated, confused and amnestic for the event. His trauma bayGCS was 15 and he had a moderate sized left scalp hematoma on physicalexamination. A. His head CT findings included a comminuted minimallydisplaced fracture of the left occipitoparietal bone with extension tothe anterior aspect of the left temporal bone. There was also a smallunderlying left subdural hematoma with pneumocephalus. There was partialopacification of the left mastoid air cells, and a non-displacedfracture through the tympanic roof could not be completely excluded. Hehad no significant ophthalmic history other than eye pressure at thetime of recruitment, and his last optometric visit was a year prior. Hiscranial trauma history included that 1.5 years ago he fell with loss ofconsciousness. Medications administered up to 24 hours prior torecruitment included levetiracetam 500 mg/100, 0.82% NaCl Premix,Ondansetron 4 mg/50 mL, Acetaminophen 325 mg. B. Represents eye movementtracking box plots 1 day after injury. The patient was positive for13/22 SCAT3 symptoms with a severity score of 62/132 and GCS score of14/15. The total SAC score was 19/30. C. Represents eye movementtracking box plots 12 days after injury. The patient was positive for19/22 SCAT3 symptoms with a severity score of 81/132 and GCS score of15/15. The total SAC score was 17/30. D. Represents eye movementtracking box plots 66 days after injury. The patient was positive for19/22 SCAT3 symptoms with a severity score of 69/132 and GCS score of15/15. The total SAC score was 24/30. No medications, drugs or alcoholwere consumed in the 24 hours prior to tracking on any occasion.

FIG. 29 represents the findings from a 23 year old right-handed male whofell from height of 30 feet. The Patient was awake, alert andhypotensive in the field, GCS 14. He reported diffuse pain including inhead, no vomiting. The neurological examination was non-focal, but thepatient was intubated for chest and pelvis injuries. He had noophthalmic history other than an optometric visit 6 months prior. Hewears corrective lenses for astigmatism and reports a learningdisability. Medications administered within 24 hours prior to eyetracking included albuterol, vancomycin hydrochloride, piperacilintazobactam, aztreonam, pentacel. A. Represents eye movement tracking boxplots 8 days after injury. No SCAT was performed initially. B.Represents eye movement tracking box plots 16 days after injury. Thepatient was positive for 16/22 SCAT3 symptoms with a severity score of18/132 and GCS of 15/15. Total SAC score of 22/30. C. Represents eyemovement tracking box plots 34 days after injury. The patient waspositive for 10/22 SCAT3 symptoms with a severity score of 27/132 andGCS of 15/15. Total SAC score of 22/30. D. Represents eye movementtracking box plots 75 days after injury. The patient was positive for13/22 SCAT3 symptoms with a severity score of 39/132 and GCS of 15/15.Total SAC score of 26/30.

FIG. 30 represents the findings from a 47 year old right-handed malerecruited from the emergency room. The patient was inebriated andcrashed his bicycle into a parked truck. He was unhelmeted. He vomitedand then became unresponsive. Upon arrival, he was intubated, GCS 3T.Radiograph revealed a broken clavicle. Quantitative serum alcohol levelwas 284 mg/dl. He had no ophthalmic history following an optometricvisit many years ago. Upon recruitment 24 hours later the patient wasextubated, alert and oriented ×3. Medications administered up to 24hours prior to recruitment included claritin andhydrocodone-acetaminophen, lidocaine, etomidate, and succinylcholine. A.Represents eye movement tracking box plots a few hours after triage. Thepatient was positive for 14/22 SCAT3 symptoms with a severity score of72/132 and GCS score of 15/15. His total SAC score was 19/30. Hereported feeling severely worse than baseline. B. Represents eyemovement tracking box plots at 92 days post triage. The patient waspositive for 10/22 SCAT3 symptoms with a severity score of 40/132 andGCS score of 15/15. His total SAC score was 21/30.

FIG. 31 represents the findings from a 53 year old right-handed femalerecruited from the ER after falling on the street down bus steps,impacting her face. She denied loss of conscious or amnesia andpresented immobilized with cervical collar. On examination she had a liplaceration. She had a medical history significant for migraines andbitemporal hemianopsia due to benign pituitary adenoma. Head CT showedmoderate multifocal white matter disease to right putamen, posteriorlyin the right caudate head and left frontal corona radiate, maybeischemic in origin, and bilateral proptosis. Her last optometric visitwas one month prior to recruitment, and she wears corrective lenses andbifocal contact in right eye. Medications administered up to 24 hoursprior to recruitment included diovan, lidocaine, hydrochloide 600 mg,acetaminphen 650 mg, vitamins, and tylenol. A. Represents eye movementtracking box plots a few hours after triage. The patient was positivefor 16/22 SCAT3 symptoms with a severity score of 40/132 and GCS scoreof 15/15. The total SAC score was 23/30. B. Represents eye movementtracking box plots at 10 days post injury. The patient was positive for4/22 SCAT3 symptoms with a severity score of 17/132 and GCS score of15/15. The total SAC score was 20/30. C. Represents eye movementtracking box plots 17 days post injury. D. Represents eye movementtracking box plots at 113 days post injury. The patient was positive for16/22 SCAT3 symptoms with a severity score of 48/132 and GCS score of15/15. The total SAC score was 27/30.

FIG. 32 represents graphically that while Mill and CT can detectstructural traumatic brain injury (TBI), eye tracking can detectphysiologic disruption of cerebral function.

FIG. 33 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 34 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 35 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 36 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 37 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 38 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

FIG. 39 indicates that subjects show significantly stronger disconjugacyduring the saccades task than while performing the box, circle orreading task.

DETAILED DESCRIPTION OF THE INVENTION

Before the present methods are described, it is to be understood thatthis invention is not limited to particular methods and experimentalconditions described, as such methods and conditions may vary. It isalso to be understood that the terminology used herein is for purposesof describing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims. As used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. Thus, forexample, references to “the method” includes one or more methods, and/orsteps of the type described herein and/or which will become apparent tothose persons skilled in the art upon reading this disclosure and soforth in their entirety.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described. All publications mentioned herein areincorporated herein by reference I their entireties.

Definitions

The terms used herein have the meanings recognized and known to those ofskill in the art, however, for convenience and completeness, particularterms and their meanings are set forth below.

“Subject” or “patient” refers to a mammal, preferably a human, in needof or undergoing treatment or screening for a condition, disorder ordisease such as, for instance, increased intracranial pressure.

By “assessing central nervous system integrity” is meant identifying oneor more symptoms that may indicate a pathology of or affecting thecentral nervous system, or identifying, assessing, quantifying ordiagnosing a pathology of the central nervous system. The pathology maybe, for instance, one or more of increased intracranial pressure,hydrocephalus, concussion, dementia, schizophrenia, amyotrophic lateralsclerosis, muscular sclerosis, autism and Fragile X disease.

By “localizing a central nervous system lesion” is meant in someinstances determining information that may predict a likely position ofa lesion, for instance, determining the side of the body, for instance,left or right, where a lesion may likely be located within the centralnervous system. In other instances, “localizing a central nervous systemlesion” may mean determining a particular fossa or compartment, such as,for instance, a fascia compartment or brain ventricle in which a lesionis likely located within the central nervous system.

By “having eye movement of a first eye that is significantly differentfrom eye movement of a second eye” is meant displaying eye movement in afirst eye over 5, 10, 25, 50, 100, 1,000, 5,000, 10,000 or moreobservations, tracked with at least x, y coordinate positions, that isat least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, or 100% or morevariant compared to the corresponding eye movement observations trackedfrom the second eye. The 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, or100% or more variant may be calculated or observed either numerically orgraphically. Alternatively, “having eye movement of a first eye that issignificantly different from eye movement of a second eye” is meantdisplaying eye movement in a first eye over 5, 10, 25, 50, 100, 1,000,5,000, 10,000 or more observations, tracked with at least x, ycoordinate positions, that, when graphically displayed in a scatterplotas described herein, is at least 5°, 10°, 15°, 20°, 25°, 30°, 40°, 50°,60°, 75° or 90° or more variant compared to the corresponding eyemovement observations tracked and graphically displayed on a scatterplotas described herein from the second eye.

Elevated Intracranial Pressure

The methods described herein are distinct from conventional methods. Asapplied to determining intracranial pressure, a conventional ICP monitordetermines the brain's pressure number in one spot, an 02 monitordetermines an oxygenation number in one spot, imaging reveals what thebrain looks like, but the methods described herein provide methods fortesting for physiologic function of the cranial nerves that may reflectfactors that may delay axoplasmic transport such as elevatedintracranial pressure.

The methods described herein may be used to detect elevated intracranialpressure and assess or determine the severity of the same. Similarly,the methods described herein may be used to localize the intracranialcause of such intracranial pressure and to monitor progression oflesions or diffuse processes within the cranium. Likewise, the methodsdescribed herein may be used to detect concussion and assess ordetermine the severity of the same.

The methods described herein provide high sensitivity. No patient yetevaluated with an abnormal physical exam or films consistent withelevated ICP has had normal eye movement tracking. The methods describedherein may be used to reduce the need for CT scans among potential shuntmalfunction patients, patients with lesions causing elevatedintracranial pressure, and may be used to screen patient populationssuch as emergency room ER populations, sports participants, soldiers orother combatants, nursing home residents or other populations at riskfor falling for elevated intracranial pressure or concussion.

High resolution automated eye movement tracking, occurring over, forinstance, about 220 seconds, is a powerful tool for detectingsubclinically apparent ocular motility dysfunction, and thus aid in therapid diagnosis of elevated intracranial pressure or concussion.

While palsies of cranial nerves II, III, IV and VI have all beendescribed in patients with acute hydrocephalus (Tzekov et al., PediatricNeurosurgery 1991; 17(6):317-320 and Chou et al., Neurosurgery Clinicsof North America 1999; 10(4):587-608), the relative vulnerability ofeach nerve has not been well established. If length of exposure to thesubarachnoid space were the sole predictor of vulnerability tointracranial pressure elevation, the IVth nerve would be most vulnerable(median length 33 mm (Hanson et al., Neurology 2004; 62(1):33-36)), theIIIrd nerve would be second most vulnerable (26 mm (Adler et al.,Journal of Neurosurgery 2002; 96(6):1103-1112)) and IInd and VIth wouldbe approximately equally least vulnerable (5 to 16 mm for II (Murali, R.Injuries of the Cranial Nerves. In: Golfinos PCaJ, ed. Head Injury. 4thed. New York: McGraw Hill; 2000), and 11 mm median length for VI (Hansonet al., Neurology 2004; 62(1):33-36)).

The abducens nerve (VI) exits the brainstem from its tethering at themedullopontine junction and courses intracranially before enteringDorello's canal, where it is again tethered by fibrous and osseousstructures. Elevation of supratentorial ICP forces the parahippocampalgyri down past the free edge of the tentorium while the brainstem withthe tethered Vlth nerve moves caudally toward the foramen magnum,stretching the nerve where it enters Dorello's canal (Hanson et al.,Neurology 2004; 62(1):33-36). Posterior fossa lesions pushing thecerebellum and brainstem forward may directly compress the Vlth nerveagainst the clivus (Hanson et al., Neurology 2004; 62(1):33-36). It isalso possible that the increased reporting of Vlth nerve palsies may bedue to their easier detection on clinical examination than III and IVthnerve palsies.

The data presented herein does not feature a calibration step in eyemovement tracking. Thus patients need not reliably follow instructions,and the data does not filter out the possible effects of cranialneuropathy. Unlike other studies (Contreras et al., Brain research 2011;1398:55-63; Maruta et al., The Journal of Head Trauma Rehabilitation2010; 25(4): 293-305; Contreras et al., Journal of Biological Physics2008; 34(3-4):381-392 and Trojano et al., J Neurol 2012; (publishedonline; ahead of print)) the data presented herein does not use saccadecount or spatial accuracy as the measure. In addition to results basedon the moving aperture's periodic envelope presented in this paper, themethodology also affords a very fine-scale data showing eye movements inresponse to the successive frames of the movie itself.

The methods described herein build on pre-existing methods that rely onintact ocular motility to address clinical questions. (Lee et al., Brainresearch. 2011; 1399:59-65; Contreras et al., Brain research 2011;1398:55-63; Maruta et al., The Journal of Head Trauma Rehabilitation2010; 25(4):293-305). The methods described herein differ in severalways. First, the present methods feature diagnosing specific clinicalconditions related to vision and ocular motility reflecting the functionof cranial nerves II, III, IV, VI and associated nuclei rather thanmeasuring cognitive impairment due to primarily cortical mild tomoderate traumatic brain injury. Second, the present methods use morefine-scale information, using, for instance, about 100,000 measurementsto pull out subtle differences that can be lost through the somewhatarbitrary thresholding of velocity measures into saccades. Third, thepresent methods do not use measurements of spatial accuracy, whichrequires transforming the raw data by a series of scaling and rotatingprocesses whose effectiveness depends on the ability of their subjectsto follow precise commands reliably. In such methods previously used, itis necessary to exclude the vast majority of neurologically compromisedpatients. Further, such methods previously used lose any informationrelated to the function of cranial nerves II, III, IV and VI, becausethe spatial distortions expected to result from damage to these nervesis reversed in the process of spatial calibration.

Trojano et al., J Neurol 2012; (published online; ahead of print)recently described uncalibrated eye movement measurements in apopulation of minimally conscious and persistently vegetative patients.The methods described herein differ in several ways. First, Trojano etal. report data from 11 rather than 25 healthy control subjects. Second,Trojano et al. evaluate chronic disorders of consciousness rather thanacute changes in intracranial pressure. Third, Trojano et al. sample eyemovements at 60 Hz rather than 500 Hz, effectively reducing the power ofthe data 100-fold. Fourth, Trojano et al. report differences inon-target and off-target fixations between the groups, despite nothaving spatially calibrated the data, making these values noisy.Finally, Trojano et al. use static stimuli moving in a quasi-periodicway. The methods described herein use moving images shown within anaperture that moves periodically and allows assessing both coarse andfine eye movement characteristics in both controls and patients.

Clinical Implications

The data presented herein are consistent with compartmentalization ofsubarachnoid spaces, as several of the patients demonstrate elevated ICPon one side of the brain, but not the other. The methods for ICPassessment described herein represent a significant advantage overconventional radiographic studies because while the latter depict howthe brain appears, our technique captures how well it functions. CTscanning may require brief sedation in a pediatric population and risksradiation exposure, while MR may require prolonged sedation. Brainimaging may not be diagnostic of elevated ICP in patients withchronically enlarged ventricles without classic findings such astransependymal flow on T2 weighted MR imaging (Mizrachi et al., JNeuroophthalmol. 2006; 26(4):260-263). Patients with non-compliant andslit ventricles may also have elevated ICP in the absence ofradiographic abnormality (Engel et al., Neurosurgery 1979;5(5):549-552). Shunt tapping risks infection and malfunction,particularly in patients with slit ventricles. Invasive monitoring risksintracranial hemorrhage. Thus additional low-risk, rapid techniques forassessment of hydrocephalus or elevated ICP may be useful to thoseassessing populations at risk for these pathologies.

The methods described herein provide a useful adjunct for diagnosis ofelevated ICP and the prospective monitoring of such patients at risk forits development. No patients with elevated ICP by history, physicalexamination and radiology have demonstrated normal ocular motility,demonstrating that the methods described herein are sensitive. The datapresented herein demonstrate that patients with grossly intactextraocular movements on physical exam, and relatively minimal changesin pathology, may have profound disruption on high resolution tracking.

The methods described herein provide a useful adjunct for diagnosis ofconcussion and prospective monitoring of such patients at risk fordeveloping the same. The data presented herein demonstrate that patientswith grossly intact extraocular movements on physical exam, andrelatively minimal changes in pathology, may have profound disruption onhigh resolution tracking.

Given the diverse baseline ocular pathology of hydrocephalic patientsalone (Dennis et al., Arch Neurol. October 1981; 38(10):607-615; Zeineret al., Childs Nerv Syst. 1985; 1(2):115-122 and Altintas et al.,Graefe's archive for clinical and experimental ophthalmology=Albrechtvon Graefes Archiv fur klinische and experimentelle Ophthalmologic.2005; 243 (12): 1213-1217), tracking results may need to be compared toeach patient's own baseline data. Similarly subjects with a history oftraumatic brain injury may have tracking results that may need to becompared to each patient's own baseline data.

The data presented herein demonstrates in part that it is possible todiagnose elevated intracranial pressure and concussion by analysis ofeye movements during watching of a video. The methods described hereinare significantly different from other technologies since imagingstudies enable one to see the brain and invasive techniques enabledetermination of an arbitrary pressure or oxygenation number. Themethods described herein actually assess physiologic functioning.

The methods described herein have many clinical applications including,for instance, i) assessing function of cranial nerves II, III, IV andVI, and perhaps even VII, VIII, and/or X; ii) detecting andquantitatively monitoring any process impeding or improving the functionof the above (e.g. demonstrating elevated ICP or increased brain masseffect, that may be applied to such things as aneurysms, multiplesclerosis, sarcoidosis, tumors, aging, alcohol abuse,intoxicants/narcotics, etc.), iii) localizing pathology and identifyingthe nature of that pathology within the brain (e.g. differentiatingbetween lesions that compress nerves and those that only create masseffect or elevate ICP far away); iv) monitoring patients via homecomputer/webcam, in-hospital or outpatient “TV shows” that perform“neuro-checks” on a regular basis; v) quantitatively measuring outcomefor assessment of persistently vegetative and minimally conscious state,aphasia, and recovery from brain injury, particularly concussion; vi)characterizing types of aphasia and localizing pathology; vii)quantitatively assessing dementia/cognitive function andneurodegenerative diseases. Likewise, the methods described herein mayprovide means for in-person screening such as to, for example, assessvision, assess ocular motility, and assess cognitive dysfunction allrelatively simultaneously (e.g. for a driver's or pilot's license,employment etc.). Further, the methods described herein may be used toassess variance, which appears to increase with cognitive decay. Thiscould be used, for instance, to target advertising by stratification ofintelligence. Further, the methods described herein may be used toassess disconjugate gaze, that apparently increases with cognitivedecay. Still further, the methods described herein may be used forintelligence or neurologic function testing.

Conjugacy of Eye Movement

The present invention features a novel eye movement tracking method thatis useful for quantitating gaze conjugacy, and thus disconjugacy, duringnaturalistic viewing. It may be performed while a subject watchestelevision or a video moving inside an aperture with a set trajectoryfor about 220 seconds at a fixed distance from a viewing monitor. It mayalso be performed as the subject views natural stimuli over time. Theposition of each pupil may be recorded over time elapsed as the videotravels on its time course, enabling detection of impaired ability tomove the pupils relative to time and therefore relative to each other.This method has high test-retest reliability in control subjects withoutsignificant neurologic or ophthalmic impairments using both a stationaryand portable eye tracking device.

Eye movement tracking for neuropsychiatric and brain injury research(Heitger, et al., Brain, 2009; 132: 2850-2870; Maruta, et al., J HeadTrauma Rehabil., 2010; 25: 293-305) has been performed for nearly 30years and can evaluate smooth pursuit, saccades, fixation, pupil sizeand other aspects of gaze. Spatial calibration of the eye tracker isgenerally performed for each individual being tracked. With calibration,the eye-tracker measures the relative position of pupil and cornealreflection for a period of about 400-800 ms while the subject looks at atarget or targets of known position to generate meaningful spatialcoordinates during subsequent pupil movement. The process of spatialcalibration implies relatively preserved neurologic function because itrequires that the subject is able to follow commands and look atspecific points.

The process of spatial calibration may mask deficits in ocular motility.If there is a persistent and replicable weakness in movement of an eye,the camera may interpret the eye's ability to move in the direction ofthat weakness as the full potential range of motion in that directiondue to the calibration process. In other words if the subject isdirected to look at a position but consistently only moves halfwaythere, the calibration process may account for that when trackingsubsequent eye movements and interpret movements to the halfway point asoccurring at the full range of normal motion. If during calibration oneeye only makes it halfway to the target, but the other eye is fullythere, the camera may interpret both eyes as being together when oneperforms half the eye movement as the other. Thus binocular spatialcalibration may preclude detection of disconjugate gaze unless each eyeis calibrated separately using a dichoptic apparatus (Schotter, et al.,PLoS One, 2012; 7: e35608).

The present invention provides a novel technique for non-spatiallycalibrated tracking performed while subjects watch a music video movinginside an aperture on a computer monitor. The aperture moves around themonitor periphery at a known rate so that the position of the pupil canbe predicted at any given time based on the time elapsed since the startof the video. By using elapsed time, rather than spatial calibration,the method detects impaired ability to move one pupil relative to theother. Uncalibrated tracking not only does not compensate for impairedmotility, but also can be used in patients who do not follow commandssuch as aphasics, foreign-language speakers, persistently vegetativeindividuals and small children. It can also be used on animals.

If the subject's eyes are positioned about 55 cm from the center of the30×35 cm viewing monitor, the method and associated algorithm elicitspupil movement in a maximum range of about 15° in any direction frommidposition, or approximately 30° total from top to bottom or side toside. Thus, in some instances, the method and associated algorithm maynot require or assess the full range of ocular motility, nor the entirevisual field. Use of a larger monitor, or one positioned closer to thesubject would enable assessment of these.

The observed and measured conjugacy was significantly higher in thehorizontal plane than vertical. This may reflect any of multiplefactors: (1) the shape of the monitor was not a perfect square butrather a 17″ diameter rectangle. Each side was traversed in 10 secondsso the eyes had a greater distance to travel horizontally thanvertically. Because the eyes were moving faster horizontally they maypossibly be more conjugate. (2) Humans have stronger event relateddesynchronization on electroencephalogram with horizontal versusvertical eye movements (Kaiser, et al., Clin Neurophysiol., 2009; 120:1988-1993). Humans may have evolved to have higher conjugacy in thehorizontal plane than in the vertical because more prey and predatorsare likely to be at near the same altitude rather than above or below.Other species have demonstrated differences in vertical versushorizontal eye movements (Lisberger, et al., J Neurophysiol., 1989; 61:173-185). (3) The control population is predominantly English speakingand thus reads from left to right, and reads faster horizontally thanvertically (Seo, et al., Vision Res., 2002; 42: 1325-1337). Testing of apopulation that reads vertically may potentially yield higher verticalconjugacy.

The technique described herein differs from uncalibrated tracking usingstatic stimuli for on-target and off-target fixations in a population ofminimally conscious and persistently vegetative patients that have openeyes (Trojano, et al., J Neurol., 2012 (published online; ahead ofprint)). The moving images shown within an aperture that movesperiodically allow assessing both coarse and fine eye movementcharacteristics in both controls and neurologically impaired subjects.Unlike other studies (Contreras, et al., Brain Res., 2011; 1398: 55-63;Contreras, et al., J Biol Phys., 2008; 34: 381-392; Maruta, et al., JHead Trauma Rehabil., 2010; 25: 293-305; Trojano, et al., J Neurol.,2012 (published online; ahead of print)) the present methods do not usesaccade count or spatial accuracy which requires transformation of rawdata by a series of scaling and rotating processes whose effectivenessdepends on the ability of their subjects to follow precise commandsreliably. The present methods also differ from gaze estimation, whichrequires either a fixed head position or multiple light sources andcameras to localize the pupil (Guestrin, et al., IEEE Trans Biomed Eng.,2006; 53: 1124-1133).

Video oculography is a relatively newer technique that uses infraredcameras mounted in goggles to track the center of the pupil's positionas the eye moves. It has been demonstrated to be useful in screening forneurovestibular and labyrinthine dysfunction and most recently indistinguishing these from vertebrobasilar stroke (Newman-Toker, et al.,Stroke, 2013; 44: 1158-1161). Video oculography generally relies onspatial calibration (Hong, et al., Behav Res Methods, 2005; 37: 133-138;Schreiber, et al., IEEE Trans Biomed Eng., 2004; 51: 676-679). The useof our non-calibrated stimulus algorithm with video oculography ratherthan a sole eye tracking camera might be an interesting subject forfuture study.

The methods described herein provide both sensitivity and specificity.Because so many different cortical functions are required for watching avideo, any process impeding global cranial function or specific cranialnerve function will likely be revealed by the present methods. Trackingmay be confounded in patients with a history of prior brain insult, whoare intoxicated, or are under the influence of pharmacologic agents.Patients' cognitive abilities, attention span and distractibility willimpact the quality of ocular motility data.

The methods described herein are useful for screening for strabismus. Ina population of 14,006 consecutive patients examined at a pediatric eyeclinic in Rome, 2.72% demonstrated either A or V-pattern strabismus(Dickmann, et al., Ophthalmic Epidemiol., 2012; 19: 302-305). A-patternwas associated with a greater prevalence of neurological impairment,hydrocephalus and meningomyelocele, while those with V-pattern exhibiteda greater prevalence of craniosynostosis and malformative syndromes(Dickmann, et al., Ophthalmic Epidemiol., 2012; 19: 302-305). Delays intreatment of strabismus onset following binocular vision maturation maybe associated with permanent disruption of stereopsis and sensory fusion(Fawcett, Curr Opin Ophthalmol., 2005; 16: 298-302).

Given the relatively low prevalence of strabismus, the methods describedherein are useful for the rapid automated assessment of acquireddisconjugacy. Such disconjugacy may be due to neurologic causesincluding trauma, hydrocephalus, demyelination, inflammation, infection,degenerative disease, neoplasm/paraneoplastic syndrome, metabolicdisease including diabetes, or vascular disruption such as stroke,hemorrhage or aneurysm formation. Disconjugacy may also be due toophthalmologic causes such as conjunctivitis, ophthalmoplegia, ocularinjury or other diseases. As such, the methods described herein areuseful for screening for strabismus or congenital disconjugate gaze,screening for acquired disconjugate gaze due to neurologic causesincluding trauma, hydrocephalus, demyelination, inflammation, infection,degenerative disease, neoplasm/paraneoplastic syndrome, metabolicdisease including diabetes, or vascular disruption such as stroke,hemorrhage or aneurysm formation. Disconjugacy may also be due toophthalmologic causes such as conjunctivitis, ophthalmoplegia, ocularinjury or other diseases, and assessing reading/learning disorders.

Binocular Eye Movement Monitoring

When the human brain is physiologically intact, the eyes move togetherwith a conjugate gaze. Only by deliberate conscious effort can anindividual overcome this mechanism (eg when they deliberately “cross”the eyes.) A failure of the eyes to move in complete synchrony is calleddisconjugate gaze.

Binocular tracking may be used to compare the non-spatially calibratedtrajectory of one eye to the other. Subtle differences between thetrajectories of the two eyes may be detected. These differences providevaluable information regarding the physiologic function or dysfunctionof the movement of one eye relative to the other. In the absence ofknown structural ocular injury, such differences reflect physiologicdifferences in the function of the two sides of the brain. Since brainlesions due to stroke, trauma or concussion, tumors, demyelinatingdisease, hydrocephalus, degenerative disease, etc. are rarely completelysymmetric, comparing the eye movement of one eye to the eye movement ofthe other eye may be used to either confirm the presence of a lesion, todifferentiate the existence of a lesion from other more global factorsthat may affect a person's ability to participate in an eye trackingtask, such as fatigue, intoxication, medications, drug abuse,malingering, or lack of willingness to participate in an eye trackingtask.

Thus binocular tracking and directly comparing the trajectories obtainedover time, rather than with spatial calibration, may be used to diagnosepathology and to distinguish between these diagnoses and global factorsthat may impact eye tracking. In addition to or instead of an eyetracking camera, a video oculography device such as goggles may be usedto evaluate eye movements over time rather than with spatialcalibration. The eye tracking device may also be located remotely andfunction via the internet or other visualization mechanism.

Computing System

A computing system according to the invention is described in FIGS.13-14 Implementations of the observer matter and the functionaloperations described herein can be implemented in other types of digitalelectronic circuitry, or in computer software, firmware, or hardware,including the structures disclosed in this specification and theirstructural equivalents, or in combinations of one or more of them. Thecomputer system or computing device 1000 can be used to implement adevice that includes the processor 106 and the display 108, the eyemovement/gaze tracker component 104, etc. The computing system 1000includes a bus 1005 or other communication component for communicatinginformation and a processor 1010 or processing circuit coupled to thebus 1005 for processing information. The computing system 1000 can alsoinclude one or more processors 1010 or processing circuits coupled tothe bus for processing information. The computing system 1000 alsoincludes main memory 1015, such as a random access memory (RAM) or otherdynamic storage device, coupled to the bus 1005 for storing information,and instructions to be executed by the processor 1010. Main memory 1015can also be used for storing position information, temporary variables,or other intermediate information during execution of instructions bythe processor 1010. The computing system 1000 may further include a readonly memory (ROM) 1010 or other static storage device coupled to the bus1005 for storing static information and instructions for the processor1010. A storage device 1025, such as a solid state device, magnetic diskor optical disk, is coupled to the bus 1005 for persistently storinginformation and instructions.

The computing system 1000 may be coupled via the bus 1005 to a display1035, such as a liquid crystal display, or active matrix display, fordisplaying information to a user. An input device 1030, such as akeyboard including alphanumeric and other keys, may be coupled to thebus 1005 for communicating information and command selections to theprocessor 1010. In another implementation, the input device 1030 has atouch screen display 1035. The input device 1030 can include a cursorcontrol, such as a mouse, a trackball, or cursor direction keys, forcommunicating direction information and command selections to theprocessor 1010 and for controlling cursor movement on the display 1035.

According to various implementations, the processes described herein canbe implemented by the computing system 1000 in response to the processor1010 executing an arrangement of instructions contained in main memory1015. Such instructions can be read into main memory 1015 from anothercomputer-readable medium, such as the storage device 1025. Execution ofthe arrangement of instructions contained in main memory 1015 causes thecomputing system 1000 to perform the illustrative processes describedherein. One or more processors in a multi-processing arrangement mayalso be employed to execute the instructions contained in main memory1015. In alternative implementations, hard-wired circuitry may be usedin place of or in combination with software instructions to effectillustrative implementations. Thus, implementations are not limited toany specific combination of hardware circuitry and software.

Implementations of the observer matter and the operations describedherein can be implemented in digital electronic circuitry, or incomputer software, firmware, or hardware, including the structuresdisclosed in this specification and their structural equivalents, or incombinations of one or more of them. The observer matter describedherein can be implemented as one or more computer programs, i.e., one ormore modules of computer program instructions, encoded on one or morecomputer storage media for execution by, or to control the operation of,data processing apparatus. Alternatively or in addition, the programinstructions can be encoded on an artificially-generated propagatedsignal, e.g., a machine-generated electrical, optical, orelectromagnetic signal that is generated to encode information fortransmission to suitable receiver apparatus for execution by a dataprocessing apparatus. A computer storage medium can be, or be includedin, a computer-readable storage device, a computer-readable storagesubstrate, a random or serial access memory array or device, or acombination of one or more of them. Moreover, while a computer storagemedium is not a propagated signal, a computer storage medium can be asource or destination of computer program instructions encoded in anartificially-generated propagated signal. The computer storage mediumcan also be, or be included in, one or more separate components or media(e.g., multiple CDs, disks, or other storage devices). Accordingly, thecomputer storage medium is both tangible and non-transitory.

The operations described herein can be performed by a data processingapparatus on data stored on one or more computer-readable storagedevices or received from other sources.

The term “data processing apparatus” or “computing device” encompassesall kinds of apparatus, devices, and machines for processing data,including by way of example a programmable processor, a computer, asystem on a chip, or multiple ones, or combinations of the foregoing.The apparatus can include special purpose logic circuitry, e.g., an FPGA(field programmable gate array) or an ASIC (application-specificintegrated circuit). The apparatus can also include, in addition tohardware, code that creates an execution environment for the computerprogram in question, e.g., code that constitutes processor firmware, aprotocol stack, a database management system, an operating system, across-platform runtime environment, a virtual machine, or a combinationof one or more of them. The apparatus and execution environment canrealize various different computing model infrastructures, such as webservices, distributed computing and grid computing infrastructures.

A computer program (also known as a program, software, softwareapplication, script, or code) can be written in any form of programminglanguage, including compiled or interpreted languages, declarative orprocedural languages, and it can be deployed in any form, including as astand-alone program or as a module, component, subroutine, object, orother unit suitable for use in a computing environment. A computerprogram may, but need not, correspond to a file in a file system. Aprogram can be stored in a portion of a file that holds other programsor data (e.g., one or more scripts stored in a markup languagedocument), in a single file dedicated to the program in question, or inmultiple coordinated files (e.g., files that store one or more modules,sub-programs, or portions of code). A computer program can be deployedto be executed on one computer or on multiple computers that are locatedat one site or distributed across multiple sites and interconnected by acommunication network.

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processors of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read-only memory ora random access memory or both. The essential elements of a computer area processor for performing actions in accordance with instructions andone or more memory devices for storing instructions and data. Generally,a computer will also include, or be operatively coupled to receive datafrom or transfer data to, or both, one or more mass storage devices forstoring data, e.g., magnetic, magneto-optical disks, or optical disks.However, a computer need not have such devices. Moreover, a computer canbe embedded in another device, e.g., a mobile telephone, a personaldigital assistant (PDA), a mobile audio or video player, a game console,a Global Positioning System (GPS) receiver, or a portable storage device(e.g., a universal serial bus (USB) flash drive), to name just a few.Devices suitable for storing computer program instructions and datainclude all forms of non-volatile memory, media and memory devices,including by way of example semiconductor memory devices, e.g., EPROM,EEPROM, and flash memory devices; magnetic disks, e.g., internal harddisks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROMdisks. The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, implementations of the observermatter described in this specification can be implemented on a computerhaving a display device, e.g., a CRT (cathode ray tube) or LCD (liquidcrystal display) monitor, for displaying information to the user and akeyboard and a pointing device, e.g., a mouse or a trackball, by whichthe user can provide input to the computer. Other kinds of devices canbe used to provide for interaction with a user as well; for example,feedback provided to the user can be any form of sensory feedback, e.g.,visual feedback, auditory feedback, or tactile feedback; and input fromthe user can be received in any form, including acoustic, speech, ortactile input.

Described herein are many specific implementation details, these shouldnot be construed as limitations on the scope of any inventions or ofwhat may be claimed, but rather as descriptions of features specific toparticular implementations of particular inventions. Certain featuresdescribed herein in the context of separate implementations can also beimplemented in combination in a single implementation. Conversely,various features described in the context of a single implementation canalso be implemented in multiple implementations separately or in anysuitable subcombination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a subcombination or variation of a subcombination.

Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. In certain circumstances, multitasking and parallel processingmay be advantageous. Moreover, the separation of various systemcomponents in the implementations described above should not beunderstood as requiring such separation in all implementations, and itshould be understood that the described program components and systemscan generally be integrated in a single software product or packagedinto multiple software products.

The Relationship of Aspect Ratio and Variance as Measures of the Signal

When the (x,y) pairs are plotted to show the ‘box plots,’ they have beenpreprocessed because the absolute values of the raw data are of limiteduse since changes in the signal over time are most important. There aremany ways to normalize data, including dividing by the mean, by thestandard deviation, or by the variance. Furthermore, the standarddeviation or variance can be computed for all the data at once or x canbe normalized using the variance of x and y can be normalized using thevariance of y. Any normalization procedure for periodic data likelyincludes subtracting the mean, so the signal can be plotted as signalchange alternating around zero. All of these transformations areconventional and widely used in data analysis by those of ordinary skillin the art. The details depend on the question being asked and the typeof modeling or statistical testing being used.

In creating the box plots described herein, the raw data is preprocessedas follows: for the x (horizontal) and y (vertical) vectorsindependently, the mean is subtracted and divided by the standarddeviation (which is the square root of the variance). This puts all thedata in the same relative frame (zero-mean, max and min about 1 and −1).This is the reason the boxes look square (even if the stimuluspresentation monitor is not square).

This means that ‘long’ and ‘short’ sides are reflecting relativevariability. If the variability is high, the denominator is high and themeasure value low. So, for example, if the variability of the horizontal(x) data is high relative to the variability of the vertical (y) data,the horizontal aspect of the box will be relatively smaller, and theresult will be a tall skinny box (higher aspect ratio). Conversely, ifthe variability of the vertical (y) data is high relative to thevariability of the horizontal (x) data, the vertical range will bereduced and the result will be a short fat box (lower aspect ratio).

Thus, particular implementations of the observer matter have beendescribed. Other implementations are within the scope of the followingclaims. In some cases, the actions recited in the claims can beperformed in a different order and still achieve desirable results. Inaddition, the processes depicted in the accompanying figures do notnecessarily require the particular order shown, or sequential order, toachieve desirable results. In certain implementations, multitasking andparallel processing may be advantageous.

Disconjugate Eye Tracking Assessment

The methods described herein provide means for assessing or quantifyingdisconjugate gaze or disconjugate eye movement. These means featurereceiving an array of pupil x and y coordinates that may be generated orobtained according to the methods described herein. These coordinatesmay be be averaged across, for instance, five eyebox trajectory cycles.Formulaically this can be represented as as follows:

${X_{{Avg},{ik}} = \frac{\sum\limits_{j = 1}^{5}\; X_{ijk}}{5}},{{{for}\mspace{14mu} {all}\mspace{14mu} i} = {1\text{:}N}},{k = {1\text{:}2}},$

where X_(ijk) refers to the x-coordinate of the pupil, and k refers tothe left or right eye of a subject. The difference in the x and yposition, for the left and right eye, may then be computed. This vectorof difference may then be plotted graphically for purposes of assessmentand interpretation. To have a single metric expressing the level ofpupil disconjugation, a variance of the data may be computed withrespect to an expected mean of zero. This is significant because thecode assumes that a healthy subject has zero lateral or longitudinalpupil position difference between each eye. The variance may be computedas follows:

${Var}_{x} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}\; {\left( {X_{{Avg},i} - 0} \right)^{2}.}}}$

The total variance may be computed as follows:

Var_(Tot)−Var_(x)+Var_(y).

The variance in X, Y, and the total variance may be plotted in order toassess the amount of disconjugation (i.e. disconjugate gaze) present ina subject.

Conjugacy of Eye Movement

The methods described herein may identify strabismus. In a population of14,006 consecutive patients examined at a pediatric eye clinic in Rome,2.72% demonstrated either A or V-pattern strabismus (Dickmann, et al.,Ophthalmic Epidemiol., 2012; 19: 302-305). A-pattern was associated witha greater prevalence of neurological impairment, hydrocephalus andmeningomyelocele, while those with V-pattern exhibited a greaterprevalence of craniosynostosis and malformative syndromes (Dickmann, etal., Ophthalmic Epidemiol., 2012; 19: 302-305). Delays in treatment ofstrabismus onset following binocular vision maturation may be associatedwith permanent disruption of stereopsis and sensory fusion (Fawcett,Curr Opin Ophthalmol., 2005; 16: 298-302).

Given the relatively low prevalence of strabismus, the methods describedherein are useful for the rapid automated assessment of acquireddisconjugacy. Such disconjugacy may be due to neurologic causesincluding trauma, hydrocephalus, demyelination, inflammation, infection,degenerative disease, neoplasm/paraneoplastic syndrome, metabolicdisease including diabetes, or vascular disruption such as stroke,hemorrhage or aneurysm formation. Disconjugacy may also be due toophthalmologic causes such as conjunctivitis, ophthalmoplegia, ocularinjury or other diseases. The methods described herein may featureassessing conjugacy or disconjugacy of eye movement in correlation withstructural and non-structural traumatic brain injury, includingconcussion or blast injury.

Structurally and Non-Structurally Brain Injured Subjects

A purpose of the prospective observational study described herein was toquantitate differences in eye tracking of structurally andnon-structurally brain injured subjects relative to non-brain but bodilyinjured and healthy non-injured controls to identify the eye trackingparameters associated with structural and non-structural injury. Anotherpurpose was to identify a correlation between impaired eye tracking andclinical neurologic functioning. Eye tracking and clinical concussionassessments were performed on 44 injured subjects, and eye tracking wasperformed only on 31 healthy normal controls. 51 eye tracking parameterswere assessed in each patient. 10 parameters showed statisticallysignificant differences between negative controls (healthy normal peopleand corporally injured trauma patients) and both positive controls(patients with structural brain injury) and patients with non-structuralbrain injury. 8 additional parameters showed statistically significantdifferences between negative controls (healthy normal people andcorporally injured trauma patients) and patients with either structuralor non-structural brain injury. 10 of the eye tracking measures showedstatistically significant correlation between SCAT or SAC scores,demonstrating that these eye tracking parameters correlated with avalidated clinical outcome measure.

In order to assess ocular motility including the function of cranialnerves III, IV, and VI and associated nuclei, a novel technique forautomated eye movement tracking was developed using temporal rather thanspatial calibration. The position of the pupil is predicted based ontime elapsed since the start of the video rather than spatialcalibration, enabling detection of impaired ability to move the pupilrelative to normal controls or the opposite eye. Temporal calibrationoffers the additional advantage of utility to populations that may notbe willing or able to cooperate with calibration instructions such asyoung children, foreign-language speakers, minimally conscious persons,or aphasics.

The data presented herein quantitates differences in eye tracking ofstructurally and non-structurally brain injured subjects relative tonon-brain but bodily injured and healthy non-injured controls toidentify the parameters associated with structural and non-structuralinjury. The data presented herein further establish a correlationbetween impaired eye tracking and clinical neurologic functioning.

General Quantification Methods

Raw x and y cartesian coordinates of pupil position are collected andstored in a one-dimensional vector:

x _(i),  (1)

y _(i).  (2)

This data is normalized according to the following form:

$\begin{matrix}{{{\overset{\_}{x}}_{i} = \frac{x_{i} - {{Means}(x)}}{\sigma_{x}}},} & (3) \\{{\overset{\_}{y}}_{i} = {\frac{y_{i} - {{Means}(y)}}{\sigma_{y}}.}} & (4)\end{matrix}$

Index i corresponds to an individual data point. The size of i dependson the eye tracking hardware capture frequency and the time of tracking.The data is then sorted by eye (j=1:2, left, right), cycle (currentstimulus method features an aperture that moves around the computerscreen for five cycles) (k=1:5, first, second, third, fourth, fifth) andbox segment (1=1:4, top, right, bottom, left). Implicit, is that each j,k, l has its own data points, n, whose size is also governed by thehardware tracking frequency and time length.

x _(i) →

x _(j,k,l),  (5)

y _(i) →

y _(j,k,l),  (6)

Individual Metrics

Segment Mean

x _(j,k,l),  (7)

y _(j,k,l),  (8)

Corresponds to the arithmetic average of all data points on each segmentl for all j, k. The result is one number representing each segment l.

Median

Corresponds to the statistical median of all data points on each segmentl for all j, k. The result is one number representing each segment l.

x _(j,k,l),  (9)

y _(j,k,l),  (10)

Segment Variance

Var(

x _(j,k,l)),  (11)

Var(

y _(j,k,l)),  (12)

Corresponds to the statistical variance of all data points on eachsegment l for all j, k. The result is one number representing eachsegment l.

Specific Metrics

L.varYtop=Var(

y _(1,average) _(k=1:5,1) )  (13)

R.varYtop=Var(

y _(2,average) _(k=1:5,1) )  (14)

L.varXrit=Var(

x _(1,average) _(k=1:5,2) )  (15)

R.varXrit=Var(

x _(2,average) _(k=1:5,2) )  (16)

L.varYbot=Var(

y _(1,average) _(k=1:5,3) )  (17)

R.varYbot=Var(

y _(2,average) _(k=1:5,3) )  (18)

L.varXlef=Var(

x _(1,average) _(k=1:5,4) )  (19)

L.varXlef=Var(

x _(2,average) _(k=1:5,4) )  (20)

L.varTotal=Average(Var(

x _(1,average) _(k=1:5) )+Var(

y _(1,average) _(k=1:5) ))  (21)

R.varTotal=Average(Var(

x _(2,average) _(k=1:5) )+Var(

y _(2,average) _(k=1:5) ))  (22)

Segment Standard Deviation

σ

_(x) _(j,k,l) ,  (23)

σ

_(y) _(j,k,l) ,  (24)

Corresponds to the statistical standard deviation of all data points oneach segment l for all j, k. The result is one number representing eachsegment l.

Segment Skew

Skew(

x _(j,k,l))=

x _(j,k,l) −

x _(j,k,l),  (25)

Skew(

y _(j,k,l))=

y _(j,k,l) −

y _(j,k,l).  (26)

Corresponds to the statistical skew (how far the mean is from themedian) of all data points on each segment l for all j, k. The result isone number representing each segment l.

Specific Metrics

L.SkewTop=Skew(

y _(1,average) _(k=1:5,1) )  (27)

R.SkewTop=Skew(

y _(2,average) _(k=1:5,1) )  (28)

L.SkewRit=Skew(

x _(1,average) _(k=1:5,2) )  (29)

R.SkewRit=Skew(

x _(2,average) _(k=1:5,2) )  (30)

L.SkewBot=Skew(

y _(1,average) _(k=1:5,3) )  (31)

R.SkewBot=Skew(

y _(2,average) _(k=1:5,3) )  (32)

L.SkewLef=Skew(

x _(1,average) _(k=1:5,4) )  (33)

R.SkewLef=Skew(

x _(2,average) _(k=1:5,4) )  (34)

Segment Normalized Skew

$\begin{matrix}{\mspace{79mu} {{{{SkewNorm}\left( {\overset{\_}{x}}_{j,k,l} \right)} = \frac{{Skew}\left( {\overset{\_}{x}}_{j,k,l} \right)}{\sigma \text{?}}},}} & (35) \\{\mspace{79mu} {{{SkewNorm}\left( {\overset{\_}{y}}_{j,k,l} \right)} = {{\frac{{Skew}\left( {\overset{\_}{y}}_{j,k,l} \right)}{\sigma \text{?}}.\text{?}}\text{indicates text missing or illegible when filed}}}} & (36)\end{matrix}$

Specific Metrics

L.SkewTopNorm=SkewNorm(

y _(1,average) _(k=1:5,1) )  (37)

R.SkewTopNorm=SkewNorm(

y _(2,average) _(k=1:5,1) )  (38)

L.SkewRitNorm=SkewNorm(

x _(1,average) _(k=1:5,2) )  (39)

R.SkewRitNorm=SkewNorm(

x _(2,average) _(k=1:5,2) )  (40)

L.SkewBotNorm=SkewNorm(

y _(1,average) _(k=1:5,3) )  (41)

R.SkewBotNorm=SkewNorm(

y _(2,average) _(k=1:5,3) )  (42)

L.SkewLefNorm=SkewNorm(

x _(1,average) _(k=1:5,4) )  (43)

R.SkewLefNorm=SkewNorm(

x _(2,average) _(k=1:5,4) )  (44)

Box Height

BoxHeight_(j,k) =

y _(j,k,1) −

y _(j,k,3)  (45)

Box Width

BoxWidth_(j,k) =

x _(j,k,2) −

x _(j,k,4)  (46)

Box Aspect Ratio

$\begin{matrix}{{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}} & (47)\end{matrix}$

Box Area

BoxArea_(j,k)=BoxHeight_(j,k)×BoxWidth_(j,k)  (48)

Conjugacy

The five cycles are averaged together to give one averaged cycle,rendering:

x _(j)

,  (49)

y _(j)

.  (50)

Then the data from the right eye is subtracted from the left eye toobtain a delta value:

x

=

x _(1,l) −

x _(2,l)  (51)

y

=

y _(1,l) −

y _(2,l)  (52)

Here x represents the left normalized raw x pupil position minus theright normalized raw x pupil position. l corresponds to the top, right,bottom and left segments of the box.

Variance (Conjugacy)

The variance here does not follow the traditional form of statisticalvariance. In the traditional form, the average of the data points issubtracted from the sum of individual data points. In this case, theaverage is forced to zero, thus inferring that the hypothetical controlpatient has perfect conjugacy (left and right eye move preciselytogether).

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {var}\; X} = {{{Var}\; \left( \text{?} \right)} = \frac{{\sum\limits^{4}\; {\text{?}\left( \text{?} \right)^{2}}} - 0}{\sum\limits^{4}\; \text{?}}}},}} & (53) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {var}\; Y} = {{{Var}\; \left( \text{?} \right)} = \frac{{\sum\limits^{4}\; {\text{?}\left( \text{?} \right)^{2}}} - 0}{\sum\limits^{4}\; \text{?}}}},}} & (54) \\{\mspace{79mu} {{{TotalVariance} = {{{Conj}\mspace{11mu} {totVar}} = {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}}}},}} & (55) \\{\mspace{79mu} {{{CoVariance} = {{{Conj}\mspace{11mu} {CorrXY}} = \frac{\sum\limits^{4}\; {\text{?}\text{?}}}{{\sum\limits^{4}\; {\text{?}\text{?}}} - 1}}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (56)\end{matrix}$

Specific Metrics

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYtop}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYrit}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYbot}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYlef}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$

Variance x Ratio Top/Bottom (Conjugacy)

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtopbotRatio}} = \frac{{Var}\left( \text{?} \right)}{{Var}\left( \text{?} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (69)\end{matrix}$

Variance y Ratio Top/Bottom (Conjugacy)

$\begin{matrix}{\mspace{76mu} {{{{Conj}\mspace{11mu} {varYtopbotRatio}} = \frac{{Var}\left( \text{?} \right)}{{Var}\left( \text{?} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (70)\end{matrix}$

Variance x Ratio Left/Right (Conjugacy)

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlefritRatio}} = \frac{{Var}\left( \text{?} \right)}{{Var}\left( \text{?} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (71)\end{matrix}$

Variance y Ratio Left/Right (Conjugacy)

$\begin{matrix}{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYlefritRatio}} = \frac{{Var}\left( \text{?} \right)}{{Var}\left( \text{?} \right)}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (72)\end{matrix}$

EXAMPLES

The following examples are set forth to provide those of ordinary skillin the art with a description of how to make and use the methods andcompositions of the invention, and are not intended to limit the scopethereof. Efforts have been made to insure accuracy of numbers used(e.g., amounts, temperature, etc.) but some experimental errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, molecular weight is average molecular weight,temperature is in degrees Centigrade, and pressure is at or nearatmospheric.

Example 1 Background

Eye movements contain clinically important information aboutneurological integrity. Clinical devices may take advantage of therelative ease of automated eye-movement tracking, for applications suchas assessing recovery following clinical intervention. A technique wasdesigned that can reliably measure eye movements with precision, withoutinitial spatial calibration. We tracked eye movements without spatialcalibration in neurologically intact adults and in neurosurgicalpatients as they watched a short music video move around the perimeterof a screen for 220 s. Temporal features of the data were measured,rather than traditional spatial measures such as accuracy or speed.

The methods reliably discriminated between the presence and absence ofneurological impairment using these uncalibrated measurements. Theresults indicate that this technique may be extended to assessneurologic integrity and quantify deficits, simply by having patientswatch TV.

These methods are useful in a number of contexts, including rapidassessment of potentially neurologically injured individuals, monitoringof patients whose states might fluctuate between impairment andrecovery, and measuring the efficacy of rehabilitation or intervention.

Eye movements have long been known to contain clinically relevantinformation about neurological integrity. Assessment of ocular motilityis a standard part of any neurological exam, because it is easy andinformative. However, there are some problems with the standard clinicalexam including that it is normally administered by an expert, andgenerally is only qualitative, not quantitative.

The relative ease, portability, and noninvasiveness of automatedeye-movement tracking devices has made it a promising area oftranslational research, for applications such as testing for concussionon athletic fields and assessing recovery following clinicalintervention. Eye movement studies have provided insight into clinicalfields from psychiatry to traumatic brain injury (TBI) andrehabilitation. (Trojano, et al., J Neurol., 2012, 259(9):1888-95;Gitchel, et al., Arch Neurol., 2012, 69(8):1011-7; Qiu, et al., PLoSOne, 2011, 6(10):e25805; Plow, et al, PMR, 3(9):825-35; Heitger, et al.,Brain., 2009, 132(Pt 10):2850-70; Pearson, et al., Br J Sports Med.,2007, 41(9):610-2; Heitger, et al., J Neurol Sci., 2007, 15; 253(1-392):34-47; Suh, et al., Neurosci Lett., 2006, 401(1-2):108-13; Suh, etal., Neurosci Lett., 2006, 410(3):203-7; Heitger, et al., Brain Inj.,2006, 20(8):807-24; Yang, et al., Image and Vision Computing, 2002,20(4):273-87; and Heitger, et al., Prog Brain Res., 2002, 40:433-12 48)Studies commonly measure accuracy of spatial fixation, time spent onparticular fixation targets, and saccade count. (Trojano, et al., JNeurol., 2012, 259(9):1888-95 and Foulsham, et al., Vision Res., 2011,51(17):1920-31) Despite the promise, it has proven difficult to developclinical applications based on quantitative measurements ofeye-movements, (Heitger, et al., Prog Brain Res., 2002, 40:433-12 48 andFoulsham, et al., Vision Res., 2011, 51(17):1920-31) possibly becausespatial calibration can be difficult in clinical settings, and becausespatial calibration precludes the use of eye tracking for detection ofdysfunctional ocular motility.

The standard use of an eye-tracker requires that the system becalibrated individually for every observer at the start of everymeasurement session. Calibration involves asking the observer to look ata series of high-contrast dots displayed on a computer monitor. Thecalibration process may be repeated several times until sufficientaccuracy has been achieved. Only then can eye movements be recorded.

It has been difficult to use eye-tracking in clinical applications withobservers for whom this calibration process is difficult (e.g.,requiring many repetitions) or impossible, Calibration requires awilling observer who can follow commands reliably. Many clinicalconditions that result in a loss of neural integrity, such as stroke orbrain injury, also render the observer unwilling or unable to followinstruction.

Also problematic for using eye-tracking methods to brain injury orstroke patients, the calibration process itself may reduce thesensitivity of the eye tracking test. For example, consider a patientwith impaired vertical ocular motility. Because the calibration processassumes that the eyes cover the full range of locations mapped out bythe calibration points, it assigns the maximum pupil angle up and downincorrectly to the ‘top’ and ‘bottom’ of the monitor, respectively. Insuch instances, all future measurements for that observer are adjustedto conform to that incorrect assignment. Thus, impaired ocular motilitymay be undetected in tests that begin with a spatial calibration of theeye tracker.

Eye movement measurements may reflect severity of damage to the brain,as well as recovery following clinical intervention. The methodsdescribed herein were used to test patients from neurosurgery, emergencydepartment and ophthalmology clinics as well as a control set of healthyvolunteers. The success of the method involves two features. First, themethods described herein do not use spatial measures of accuracy as avariable of interest. By looking at eye movement trajectories in thetime domain rather than the spatial domain, it is possible to quantifymeasures that do not rely on spatial calibration. Second, the measuresare easily visualized and evaluated, making them immediately useful tothe clinician or researcher.

Methods

Subjects.

Healthy observers were recruited in New York University according to IRBapproved protocols as determined by the University Committee onActivities Involving Human Subjects (UCAIHS). All participants providedwritten informed consent, and the consent forms were approved by UCAIHS.Patients with neurological deficit were recruited from the neurosurgicalpractice at Bellevue Hospital. Written informed consent from thesubjects or their legal proxies were obtained for prospective datacollection according to guidelines established by the NW IRB.

Observers.

Because of the potential for uncalibrated eye-tracking to serve as aninitial screen, the patient population was not restricted to a specificpathology. Rather, an arbitrary sample of patients who came through theclinic was recruited. The resulting sample was representative of therange of disorders seen in the clinic.

Eye Movement Tracking.

Observers' eye movements were recorded using an Eyelink 1000 binoculareye tracker (500 Hz sampling, SR Research). All observers were seatedapproximately 55 cm from the screen. Some test patients were tracked onmultiple visits at different stages of diagnosis, surgery, and recovery.

Visual Stimulus.

The visual stimulus provided as a music video that played continuouslywhile it moved clockwise along the outer edges of a computer monitor.Observers were instructed to watch the video. The stimulus was expectedto evoke smooth pursuit eye movements as well as possible saccades andmicrosaccades as the observers scanned the video. The video waspresented in a square aperture with an area approximately ⅛ of the sizeof the screen (about 16° of visual angle). This square aperture startedat the upper left hand corner of the screen and moved at a constantspeed, taking 10 seconds to traverse each edge of the monitor. A fullcycle took 40 seconds, and five full cycles were played, for a total of200 seconds. A countdown video played in the starting position for 10seconds before the music video began, to give observers time to orientto the stimulus. Only the 200 seconds of the music video were used foranalyses. The eye tracker sampled eye position at 500 Hz, yielding100,000 samples of eye position over 200 seconds.

Axis Orientation.

The camera and monitor were securely mounted, so that ‘horizontal’ forthe camera was the same as ‘horizontal’ for the monitor. Therefore, theterms ‘horizontal’ and ‘vertical’ are defined with respect to themonitor, not with respect to head-tilt. However, the head was typicallyaligned with the monitor, and a chinrest was used with all controls andabout half of the patients, to ensure the continued alignment. Theeyetracker converted changes of pupil angle into two orthogonalcomponents which it labeled x, and y, and which in turn referred tohorizontal and vertical change, due to the linked orientation of themonitor and camera. Therefore, we also refer to horizontal and verticalcomponents as x and y respectively.

Data Preprocessing.

There was no spatial calibration so the units of the raw timecourseswere of limited value. Therefore, for each observer, the timecourseswere normalized by subtracting the mean and dividing by the standarddeviation. This was done for each timecourse independently. Thedifferent timecourses were treated as distinct data sets from the sametest patient or neurologically intact control.

Timecourses.

The normalized x- and y-timecourses were plotted across time (FIGS. 1Aand B). The clockwise movement of the visual stimulus alternated betweenhorizontal changes and vertical changes, and the x- and y-timecourses inneurologically intact observers show the same alternation.

Visualization: Scatterplots. For visualization, scatterplots of theentire time series were created by plotting the 100,000 (x,y) pairsrepresenting the two orthogonal components of the instantaneous angle ofpupil reflection over 200 seconds. In neurologically intact controls,these figures look like boxes, reflecting the timing of the visualstimulus as it moved around the screen.

Quantitative Data Analysis and Statistics.

The x- and y-trajectories were fit with sinusoidal functions. Thealternations in horizontal and vertical motion of the visual stimuluswere thought to result in eye movement trajectories that wereapproximately sinusoidal with a period of 40 s, but with differentphases for x and y. We further hypothesized that (1) the phasedifference between x and y should be 45 degrees for neurologicallyintact controls, reflecting the ¼ cycle alternation of horizontal andvertical eye movements; and (2) the model would fit data from theneurologically intact control observers better than it fit data from thepatient group.

Degree of correlation (r) with a sinusoid was calculated for 1 each timecourse. The square of this value (r2) is a measure of goodness of fit ofthe model to the data. The correlation values were used because theybetter suited for statistical analysis. Throughout the text, ‘model fit’refers to the correlation values (r):

Phase was calculated as phase of the sine function that best fit thedata. The 8 following complementary procedures were used to assess thestatistical significance of any differences in these two measures (phasedifference and model tit) as compared between the neurologically intactcontrol observers and the test patient observers.

(i) Statistical Analysis 1: Hypothesis Testing.

For each measure, a statistical test was performed to determine whetherthe data from the test patient population could have come from the sameunderlying distributions as the data from the neurologically intactcontrol population. For the phase measure, an unpaired t-test was used.For the sinusoidal fit measure, the Kruskal-s analysis of variance(ANOVA) was used which is more appropriate for data that are notnormally distributed.

(ii) Statistical Analysis 2: Fisher Transformation.

The correlation (r) values for timecourse with the best fitting sinusoidwere converted to z-scores using the Fisher transformation((½)*ln((1+r)/(1−r)). This normalization enables to complete the thirdstep of the analysis.

(iii) Statistical Analysis 3: Classification.

The Fisher z-scores provided an estimate of the probability of seeing aparticular correlation value for a given timecourse if the underlyingpopulation of timecourses had zero mean correlation (the nullhypothesis). The null hypothesis would be expected to be true fortimecourses that were not fit well by sinusoids, e.g., timecourses fromimpaired observers: Timecourses with z-scores significantly above zero(e.g., well-matched to the stimulus trajectory) would be expected tocome from unimpaired observers. A threshold of z=2 (corresponding to asignificance level of alpha=0.05) was used to calculate the specificityand sensitivity of this test, as reported in the Results following.

Results

Eye movements were highly reliable and consistent across the group ofneurologically intact control observers ( ).

Discussion

Uncalibrated tracking may provide a quantitative measure of the abilityto fixate, attend, and follow a stimulus. These date demonstrate that itis possible to collect reliable high-frequency eye movement data withoutfirst completing a spatial calibration for each observer. Many patientsare not capable of calibrated eye tracking. The ability to track eyemovements in these populations provides new insights about a variety ofdisorders that disturb the ocular-motor system, including but notlimited to brain injury, stroke, and psychiatric disorders. Possibleapplications include clinical screening, diagnosis, monitoring theefficacy of treatment, and tracking progression of impairment andrecovery.

Example 2 Materials and Methods

Subjects.

Healthy subjects were recruited in a university setting in accordancewith IRB approved protocols. All other subjects were recruited directlyfrom our neurosurgical practice. Informed consent from the subject ortheir legal proxy was obtained for prospective data collection in allcases in accordance with IRB guidelines.

Eye Movement Tracking.

The subjects' eye movements were recorded using an Eyelink 1000binocular eye tracker (500 Hz sampling, SR Research). Healthy volunteerswere seated 55 cm from the screen with their head stabilized using achinrest. Stimulus was presented on average 55 cm from patient eyes,with the presentation monitor adjusted to match gaze direction. Subjectsused a chinrest.

Innovations for Tracking Patients.

Two innovations were provided to measure ocular motility in a patientpopulation. The first was a paradigm, consisting of a stimulus and ananalysis stream that allows interpreting raw eye position data. With fewexceptions, eye movement studies analyze transformed gaze position,which involves a loss of information and excludes many patients fromstudy. A novel algorithm for looking at pupil position directly,yielding information about ocular motility was developed. A device thatcan be brought to patients was provided. With few exceptions, eyemovement data are collected using a fixed eye tracker at an unchanginglocation, which requires subjects to travel to the tracker and to usethe chair and chinrest setup that goes with it. The SR Research Eyelink1000 was adapted into a novel mobile system that allows flexibility inlocation and subject position, without sacrificing data quality.

Visual Stimulus.

A music video that moved clockwise along the outer edge of a computermonitor starting at the upper left hand corner of the screen wasprovided. Spatial calibration was not performed, and the distance variedbetween subjects, so that the size of the stimulus in degrees may onlybe approximated. For a healthy subject seated 55 cm from the screen withgood spatial calibration, the stimulus was presented in a squareaperture with an area of approximately 16 degrees (approximately ⅛ ofthe size of the screen). This square aperture, within which a musicvideo played continuously, moved across the screen at a constant speed,taking 10 s to cover each edge of the monitor. A full cycle took 40 s,and five full cycles were played, for a total of 200 s. A countdownvideo played in the starting position for 10 s before the music videobegan, to provide all subjects time to orient to the stimulus. The moviecontinued for an addition 10 seconds after the 200 s trial, to avoidboundary effects from contaminating the data. Only the 200 s of themusic video comprising 5 cycles of 40 s each were used in all analyses.At a rate of 500 Hz, this yielded 100,000 samples of eye position over200 seconds.

Data Analysis: (1) Visualization.

To create a snapshot of the data from the entire trial that provided avivid indication of whether an individual subject's ocular motilitydiffers from that of healthy controls, scatterplots of the entire timeseries were created by plotting the horizontal eye position along oneaxis and vertical eye position along the orthogonal axis. The 100,000pairs of values (x,y) were plotted representing the two components ofthe instantaneous angle of pupil reflection (horizontal, vertical) over200 seconds. In healthy controls, these figures look like boxes,reflecting the trajectory traveled by the aperture as it moved acrossthe screen. These visualizations confirmed that the raw eye traces didconform to the square spatial trajectory of the stimulus, except incases of neurological damage.

Data Analysis: (2) Time Vs. Space.

Without spatial calibration, exact measurements of error in the spatialdomain are impossible. This problem was avoided by looking at the eyemovement trajectories in the time domain, rather than the spatialdomain. By using a constantly changing stimulus (a continuously playingmovie) with a periodic envelope (the aperture trajectory), it waspossible to look at relative eye movements over time. Effectively, eachsubject's mean trajectory over the path of the aperture served as itsown calibration.

Data Analysis: (3) Statistics.

In order to quantitatively assess the statistical significance of ourresults, the distribution of certain measurements in the controlpopulation was determined, and each subject was compared with thesecontrol distributions for each measure. The stimulus trajectory wasdivided into four time components: The first arm consisted of fiverepetitions of the first 10 seconds of each rotation cycle (e.g.,seconds 1:10, 41:50, 81:90, 121:130, and 161:170). The second, third andfourth arms were defined accordingly. Two variables were evaluated: therelative variance in each arm, and the relative integrity of each arm.Relative variance was calculated as mean variance across 5 repetitionswithin an arm divided by variance of the whole time course. Integritywas calculated as the percent of missing values in each arm. We defined2 tests based on these measurements, and performed the same tests in thecontrols and the patients. The results of these tests in the controlpopulation were used to determine the control distributions. The resultsof these tests for each patient were compared to the appropriate controldistribution, and confidence intervals were defined as follows.

Integrity.

For the integrity measure, each patient's pair of values from arms 1(the top of the box) and 3 (the bottom of the box) was z-scored usingthe mean and standard deviation calculated from the control population.The resulting score indicated how different the patient values werecompared with the control values, in units of standard deviations.Because 95% of all values in a normal distribution lie within twostandard deviations of the mean, a z-score of 2 was used as asignificance threshold. Patients with z-scores above 2 in either or botharms were thus judged to have significant disturbances of ocularmotility.

Relative Variance.

Because relative variance is a ratio, it cannot be analyzed usingz-scores, since the assumption of a normal distribution does not holdfor ratios. Instead, 5,000 point distributions were generated using abootstrapping method that took 5,000 samples from 25 values randomlychosen with replacement from the 45 control values. For each subject,the relative variance in arms 1 and 3 were compared respectively withthe corresponding control distribution, and the percent of the controldistribution with variance below that of the test value was determined.A p-value of 0.05 (a widely accepted measure of statisticalsignificance) corresponds to 95% of control values falling below thetest value. Thus, subjects with variance higher than 95% of the valuesin the control distributions were determined to have significantdisturbances of ocular motility.

Units.

The units of relative variance are related to size in degree of visualangle, but are not exactly identical to degrees of visual angle, becausethere was no spatial calibration. These may be referred to astime-degrees units.

Results

Successful Tracking.

Visualization of the eye movement trajectories across healthy controlsand patients confirmed that the method successfully measured eyemovements without recourse to traditional calibration techniques.

Control Distributions.

As expected, the control distributions for the integrity measurementswere normally distributed with a mean of 0.2 and an average standarddeviation of 0.05 (5% deviation). The control distributions of relativevariance peaked at 0.25 (reflecting equal variance across the fourarms).

Patient Measurements.

The integrity measures for the ‘top’ vs. ‘bottom’ arms of the trajectoryfor each subject, in units of standard deviation, as compared with thecontrol distributions as described above were calculated. Subjects withcranial nerve palsies or mass effect showed defects in integrity of eyetracing box trajectory. Subjects with relatively greater cranial nerveII palsies due to either compression or papilledema showed streakingvertical lines due to scanning vision.

Example 3 Materials and Methods

Patient Selection.

Control subjects were employees, volunteers, visitors and patients atthe Bellevue Hospital Center recruited in accordance with InstitutionalReview Board policy. Inclusion criteria for normal control subjectswere: age 7 to 100 years, vision correctable to within 20/500bilaterally, intact ocular motility, and ability to provide a completeophthalmologic, medical and neurologic history as well asmedications/drugs/alcohol consumed within the 24 hours prior totracking. Parents were asked to corroborate details of the above forchildren aged 7-17. Exclusion criteria were history of: strabismus,diplopia, palsy of cranial nerves III, IV or VI, papilledema, opticneuritis or other known disorder affecting cranial nerve II, macularedema, retinal degeneration, dementia or cognitive impairment,hydrocephalus, sarcoidosis, myasthenia gravis, multiple sclerosis orother demyelinating disease, and active or acute epilepsy,stroke/hemorrhage or brain injury sufficiently significant to result inhospitalization. Subjects reporting any minor brain injury regardless ofloss of consciousness within the previous week were also excluded.

Additional subjects were recruited from a neurophthalmic practice alsoin accordance with Institutional Review Board policy. These subjectswere selected for participation specifically because they had knownpalsies of cranial nerves III, IV and VI respectively, or other specificocular pathology.

Visual Stimulus.

Each subjects' eye movements were recorded with an Eyelink 1000 eyetracker at a fixed distance of 55 cm from a computer monitor over a timeperiod of 220 seconds. For the stationary tracker the subject was seatedin an adjustable height chair, using an adjustable height chinrest.Portable tracker subjects were seated in either a height adjustable orheight-fixed chair, with the monitor height adjusted to the subject. Theportable tracker chinrest was attached to the monitor, while thestationary tracker chinrest was attached to the same table as thecomputer monitor. The visual stimuli were the music videos ShakiraWaka-Waka, K'naan Wavin' Flag, or the Under the Sea song from the LittleMermaid. The video was played continuously in a square aperture with anarea approximately ⅛ the screen size while moving clockwise along theouter edges of the monitor for five complete cycles of 40 seconds each.The first and last 10 seconds of each data set were discarded to yield200 seconds of data. The afferent stimulus was presented binocularly andeye tracking was performed binocularly. Subjects were not spatiallycalibrated to the tracker to enable independent analysis of each pupilposition over time.

In a separate example, subjects were assessed for gaze conjugacy using anaturalistic viewing stimulus. This consisted of watching television aseye movements were tracked over time. Subjects were not seated at afixed distance from the monitor but were able to move their heads duringviewing.

Data Analysis.

The eye tracker sampled pupil position at 500 Hz, yielding 100,000samples over 200 seconds. Scatterplots of the entire time series werecreated by plotting the 100,000 (x, y) pairs representing the twoorthogonal components of the instantaneous angle of pupil reflectionover time to create ‘box trajectories’ that reflected the temporalnature of the pupillary movement. These figures look like boxes,reflecting the timing of the aperture as it moved around the screen.

Analysis of Gaze Conjugacy.

Comparing the movement of one eye of a subject to the other eye of asubject was performed by comparing the x, y Cartesian coordinates at anytime point t. For example by subtracting the x coordinate of the lefteye from the x coordinate of the right eye or vice versa. Also bysubtracting the y coordinate of the left eye from the y coordinate ofthe right eye or vice versa. The sums of the differences between all ofthe x coordinates over the time tested informs regarding horizontalmovement of the pupil. The sums of the differences in y coordinates overtime informs regarding vertical movement of the pupil. The total sum ofthe differences between both x and y coordinates over the time testedcan be summed to obtain a measure of total disconjugacy of gaze, or asan average of five eyebox trajectory cycles formulaically represented asfollows:

${X_{{Avg},{ik}} = \frac{\sum\limits_{j = 1}^{5}\; X_{ijk}}{5}},{{{for}\mspace{14mu} {all}\mspace{14mu} i} = {1\text{:}N}},{k = {1:2}},$

where X_(ijk) refers to the x-coordinate of the pupil, and k refers tothe left or right eye of a subject. In cases where a subject's data wasmissing at any given time point in the five cycles, the denominator ofthe equation was the number of cycles where the data was present. Thedifference in the x and y position, for the left and right eye, may thenbe computed. This vector of difference may then be plotted graphicallyfor purposes of assessment and interpretation. To have a single metricexpressing the level of pupil disconjugation, a variance of the data maybe computed with respect to an expected mean of zero. This issignificant because the code assumes that a healthy subject has zerovertical or horizontal pupil position difference between each eye. Thevariance for either horizontal (x) or vertical (substitute y for x)movement may be computed as follows:

${Var}_{x} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}\; \left( {\left\lbrack {(X\rbrack_{{Avg},{i\; 1}} - X_{{Avg},{i\; 2}}} \right) - 0} \right)^{2}}}$

The total variance in both the horizontal and vertical planes may becomputed as follows:

Var_(Tot)−Var_(x)+Var_(y).

The variance in X, Y, and the total variance may be plotted in order toassess the amount of disconjugation present in a subject.

Statistical Analyses

Statistics were Evaluated Using R.

Conjugacy of eye movement versus age: Normal subjects demonstratedconjugate eye movement that was not impacted by age. A linear regressionbetween total variance and age was calculated. A linear regressiont-test was used to determine whether the slope of the regression linewas statistically significantly different from 0.

Conjugacy of eye movement compared between genders: A Welch Two Samplet-test was used to determine if the true difference between the mean ofmale total variance and the mean of female total variance wasstatistically significantly different from 0.

X (horizontal eye movement) versus Y (vertical eye movement) conjugacy:A paired t-test was used to determine if the mean of the subject-paireddifferences between the total x-variance and total y-variance wasstatistically significantly different from 0.

Test-retest on the stationary tracker and from the stationary to theportable tracker: A paired t-test was used to determine if the mean ofthe subject-paired differences between the total variances for twoseparate eyetracking sessions was statistically significantly differentfrom 0.

Results

125 unique subjects aged 7 to 75 (mean 34.3±15.7, median 28.2; 51.2%female) were surveyed regarding their past medical history (Table 1),past ophthalmic history (Table 2) and any medications, alcohol or drugsof abuse (Table 3) taken within the last 24 hours. The results indicatedthat many subjects disclosed prior medical and ophthalmic history andmedication usage.

TABLE 1 Neurologic/Cranial History Conditions/Symptoms Number ofSubjects Concussion 9 Migraines 4 Hypertensin 3 Hypothryroidism 3Unspecified Head injury 3 Vertigo 2 Diabetes Melitus 1 Dyslexia 1 SpinalInjury 1 7.8 Palsy 1 *Note: Subjects may exhist in Multiple Categories

TABLE 2 Ophthalmic History Conditions/Symptoms Number of Subjects Myopia26 Astigmatism 9 Hyperopia 6 Cataracts 5 Glaucoma 2 Keratosis 2 RetinalDetachment 2 Adie Syndrome 1 Chalzion 1 Corneal Ulcers 1 Lasik 1 OrbitalMyositis 1 Presbyopia 1 Sty 1 Trauma from foreign object 1 Other,unspecified 9 *Note: Subjects may exhist in Multiple Categories

TABLE 3 Medication/Drug Usage in last 24 hrs Drugs Number of SubjectsMultivitamin 11 Synthriod 5 Vitamin D 5 Aspirin 6 Advil 3 Lisinopril 3Lipitor 3 Simvastatin 3 Adderall 2 Calcium 2 Flovent 2Hydrocholorthiazide 2 Imuran 2 Insulin (unspecified) 2 Laxapro 2Metoprolol 2 Norvasc 2 Spironolactone 2 Yaz 2 Albuterol 1 Allegra 1Vitamin B12 1 Calcitriol 1 chondroitin 1 Citrucel 1 Clopidogrel 1Colcrys 1 Concerta 1 Cordia 1 Diovan 1 Doxycycline 1 Esomeprazole 1Ferrous Sulfate 1 Fish Oil 1 Flonase 1 Furosemide 1 Gabapentin 1Glyburide 1 Hydrocortisone 1 Kombigyze XR 1 Lantus 1 Losartan 1 Lutera 1Magnesium Oxide 1 Methimazole 1 Motrin 1 Nexium 1 Niquil 1 Nit D 1Novolog 1 OCP (unspecified) 1 Omezaprole 1 Plavix 1 Prandin 1 Prilosec 1Singulair 1 Stribild 1 Toprol 1 Trimo-San 1 Welbutrin 1 Xyzal 1 Zyprexa1 Zyrtec 1 Admit to Marijuana 1 Admit to Alcohol in past 24 6 *Note:Subjects may exhist in Multiple Categories

Normal subjects demonstrated conjugate eye movement that was notimpacted by age (FIG. 7). A linear regression t-test was used todetermine whether the slope of the relationship between total varianceand age yielded a regression line statistically significantly differentfrom 0. The test resulted in a t-statistic of −0.523 and a p-value of0.6017 showing that the slope of the regression line was notstatistically significantly different from 0. Thus in the subjectpopulation ranging in age from 7 to 75, there was no change in conjugacyof eye movements with age.

The single greatest outlier (conjugacy of 0.8214) in the controlpopulation was a 23 year old male student who wears corrective contactlenses and takes adderal for attention deficit and hyperactivitydisorder. This subject underwent repeat tracking which remaineddisconjugate, (0.2600) however less than previously. The second greatestoutlier (conjugacy 0.486) was a 39 year old male hospital employee whodenied any ophthalmic or medical history, as well as the use of alcoholor drugs in the prior 24 hours. In both of these subjects theX-conjugacy was not a statistical outlier and only the y coordinateswere disconjugate.

Normal subjects demonstrated conjugate eye movement that was notimpacted by gender (FIG. 8). A Welch Two Sample t-test with 68.49degrees of freedom resulted in a t-statistic of 0.6734 and a p-value of0.5029 showing that the difference in the means was not statisticallysignificantly different from 0.

Normal subjects demonstrated horizontal eye movement that wasstatistically highly significantly more conjugate than vertical eyemovement (FIG. 9). A paired t-test was used to determine if the mean ofthe subject-paired differences between the total x-variance and totaly-variance was statistically significantly different from 0. With 124degrees of freedom, the test resulted in a t-statistic of −3.0263 and ap-value of 0.003011 showing that the mean of the subject-paireddifferences was statistically highly significantly different from 0.Specifically, it was shown that for a particular subject, x-variance isstatistically significantly less than y-variance.

Subjects (n=27) demonstrated high test-retest reliability between twoseparate eyetracking sessions on the stationary tracker (FIG. 10). Apaired t-test was used to determine if the mean of the subject-paireddifferences between the total variances for two separate eyetrackingsessions was statistically significantly different from 0. With 26degrees of freedom, the test resulted in a t-statistic of 1.2778 and ap-value of 0.2126 showing that the mean of the subject-paireddifferences was not statistically significantly different from 0.

Subjects (n=24) demonstrated high test-retest reliability betweenseparate eyetracking sessions on the stationary tracker and the portabletracker (FIG. 11). A paired t-test with 23 degrees of freedom (n=24),resulted in a t-statistic of 1.3661 and a p-value of 0.1851 showing thatthe mean of the subject-paired differences was not statisticallysignificantly different from 0.

FIG. 1 represents the eye tracking trajectories of subjects with normalcompared to known (well-defined) neurophthalmic abnormality.

Example 4 Materials and Methods.

Four groups of subjects were selected as follows:

(1) subjects who have mild to moderate structural traumatic brain injury(TBI) as evidenced by CT scan demonstrating the presence of hemorrhage(subdural, epidural, subarachnoid or intraparenchymal), brain contusion,or skull fracture.

(2) nonstructural TBI subjects (mild TBI/concussion), meaning they showno signs of structural injury on imaging; however, they complain ofusual brain injury symptoms such as headache, dizziness, cognitiveimpairment, etc., A subject with mild traumatic brain injury is a personwho has had a traumatically induced physiological disruption of brainfunction, as manifested by at least one of the following:

-   -   a. Any period of loss of consciousness (LOC).    -   b. Any loss of memory for events immediately before or after the        accident.    -   c. Any alteration in mental state at the time of accident (i.e.        feeling dazed, disoriented, or confused).    -   d. Focal neurological deficit(s) that may or may not be        transient, but where the severity of the injury does not exceed        the following:        -   1.) Loss of consciousness of approximately 30 minutes or            less        -   2.) After 30 minutes, an initial Glasgow Coma Scale (GCS) of            13-15        -   3.) Posttraumatic amnesia (PTA) not greater than 24 hours.

(3) non-brain injured subjects that have suffered some type of injurysuch as to the extremities or other parts of the body. The subjects havesustained a blunt or penetrating trauma such as, to the corpus orextremities (i.e. car accident, falling, violent act excludinginterpersonal violence).

(4) Healthy non injured control subjects were employees, volunteers,visitors and patients with intact ocular motility, and ability toprovide a complete ophthalmologic, medical and neurologic history aswell as medications/drugs/alcohol consumed within the 24 hours prior totracking. Exclusion criteria included any minor brain injury regardlessof loss of consciousness within the previous month.

Inclusion Criteria.

All patients were recruited from the Bellevue Hospital EmergencyServices (Emergency Room and Trauma Bay), trauma service andneurosurgery service. They were between the ages of 18 and 60,consentable and able/willing to participate and meet criteria fordistribution into one of the three subject populations (structural TBI,non-structural TBI, injured/non-TBI) described above.

Exclusion Criteria.

Subjects that received minor trauma insufficiently traumatizing toresult in sufficient sequelae were excluded. Subjects suffering burns,anoxic injury or multiple/extensive injuries resulting in any medical,surgical or hemodynamic instability were also excluded. Particularly forthe purposes of eye tracking all subjects that were blind (no lightperception), missing eyes, and not opening eyes were excluded from theresearch. It is pertinent that subjects are able to detect light andhave both eyes in order for the eye tracking data to be effective andsignificant. Any physical or mental injury or baseline disabilityrendering task completion difficult was excluded, also inability toparticipate in longtitudinal care, or obvious intoxication or bloodalcohol level greater than 0.2. Pregnant individuals and prisoners werealso excluded from the study. Subjects with a history of: strabismus,diplopia, palsy of cranial nerves III, IV or VI, papilledema, opticneuritis or other known disorder affecting cranial nerve II, macularedema, retinal degeneration, dementia or cognitive impairment,hydrocephalus, sarcoidosis, myasthenia gravis, multiple sclerosis orother demyelinating disease, and active or acute epilepsy,stroke/hemorrhage or prior brain injury sufficiently significant toresult in hospitalization were also excluded.

Subjects underwent eye tracking and SCAT3 validated concussion outcomeassessment as soon as possible after their injury, and then at regularintervals during recovery (1 week and 1 month).

Eye Tracking

A portable binocular eye movement tracker was constructed by attachingan adjustable arm to a rolling cart. A computer monitor was attached tothe proximal portion of the arm, and a chinrest was attached to thedistal aspect of the arm such that the chinrest centered the subject'seyes 55 cm away from the monitor.

Visual Stimulus.

Subjects' eye movements were recorded with an Eyelink 1000 eye trackerover a time period of 220 seconds. Portable tracker subjects were seatedin either a height adjustable or height-fixed chair or bed, with themonitor height adjusted to the subject. The visual stimuli were themusic videos Shakira Waka-Waka, K'naan Wavin' Flag, Mission KashmirBhumbroo or Michael Jackson Man in the Mirror. The video was playedcontinuously in a square aperture with an area approximately 1/9 thescreen area while moving clockwise along the outer edges of the monitorfor five complete cycles of 40 seconds each. The first and last 10seconds of each data set were discarded to yield 200 seconds of data.The afferent stimulus was presented binocularly, and eye tracking wasperformed binocularly. Subjects were not spatially calibrated to thetracker to enable independent analysis of each pupil position over time.

Data Analysis.

The eye tracker sampled pupil position at 500 Hz, yielding 100,000samples over 200 seconds. Scatterplots of the entire time series werecreated by plotting the 100,000 (x,y) pairs representing the twoorthogonal components of the instantaneous angle of pupil reflectionover time to create ‘box trajectories’ that reflected the temporalnature of the pupillary movement. These figures look like boxes,reflecting the timing of the aperture as it moved around the screen.

Metrics:

51 eye-tracking parameters were measured per subject, looking atmovement in each individual eye and conjugate movement between eyes. Alldata were analyzed using XLSTAT version 2012.6.02 (Addinsoft SARL,Paris, France) and MedCalc version 12.6.1 (MedCale Software, Ostend,Belgium). A p-value of ≤0.05 was deemed as statistically significant.

Eye-tracking was performed on 46 patients and 31 controls. The patientswere assigned to 1 of 4 groups (+CT n=13, −CT n=23, corpus injury n=10,and healthy control). Eye-tracking parameters were compared among the 4groups using the Kruskal-Wallis test and multiple pair-wise wereperformed using the Steel-Dwass-Crichlow-Fligner procedure to compareindividual groups against controls.

The sports concussion assessment tool (SCAT) was administered, andstandardized assessment of concussion (SAC) scores were obtained onthirty-seven subjects. Stepwise multiple regression analysis wasperformed to evaluate the impact of each eye-tracking parameter on theSCAT and SAC scores. Parameters with p-values>0.1 were removed from themodel.

Results

Table 4 provides group means for each of the 51 measured parameters.

TABLE 4

n

 Ratio|Corpus only 10

 Ratio|−CT 23

 Ratio|+CT 12

 Ratio|Control 31

|Corpus only 10

|−CT

|+CT 12

|Control 31

|Corpus only 10

|−CT 22

|+CT 12

|Control 31

|Corpus only 10

|−CT 22

|+CT 12

|Control 31

|Corpus only 10

|−CT

|+CT 13

|Control

|Corpus only 10

|−CT 13

|+CT

|Control 31

|Corpus only

|−CT 23

|+CT 13

|Control 31

|Corpus only 10

|−CT 23

|+CT

|Corpus only 10

|−CT

|+CT 12

|Control 23

|Corpus only 10

|−CT 23

|+CT 12

|Control

|Corpus only 10

|−CT

|+CT

|Control 31

|Corpus only 10

|−CT

|+CT 12

|Control

|Corpus only 10

|−CT 23

|+CT

|Control

|Corpus only 10

|−CT

|+CT

|Control

|Corpus only 10

|−CT 23

|+CT

|Control

|Corpus only 10

|−CT

|+CT

L.varTotal|+CT 13 0.052 2.242 0.690 0.556 L.varTotal|Control 31 0.0241.252 0.218 0.259 Conj varX|Corpus only 10 0.001 0.026 0.009 0.009 ConjvarX|−CT 23 0.001 0.476 0.046 0.103 Conj varX|+CT 13 0.001 0.432 0.0790.319 Conj varX|Control 31 0.001 0.053 0.010 0.013 Conj varXtop|Corpusonly 10 0.001 0.035 0.009 0.010 Conj varXtop|−CT 23 0.001 0.193 0.0270.049 Conj varXtop|+CT 13 0.002 0.413 0.062 0.122 Conj varXtop|Control31 0.001 0.034 0.007 0.008 Conj varXrit|Corpus only 10 0.000 0.023 0.005

Conj varXrit|−CT 23 0.000 0.132 0.025

Conj varXrit|+CT 13 0.001 0.364 0.072 0.111 Conj varXrit|Control 310.000 0.093 0.010 0.021 Conj varXbot|Corpus only 10 0.000 0.069 0.0110.021 Conj varXbot|−CT 23 0.000 0.456 0.036 0.106 Conj varXbot|+CT 120.001 0.698 0.100 0.203 Conj varXbot|Control 31 0.000 0.034 0.004 0.006Conj varXlef|Corpus only 10 0.000 0.012 0.003 0.004 Conj varXlef|−CT 230.000 0.206 0.019 0.046 Conj varXlef|+CT 12 0.001 0.572 0.073 0.160 ConjvarXlef|Control 31 0.000 0.010 0.002 0.002 Conj varY|Corpus only 100.002 0.109 0.032 0.043 Conj varY|−CT 23 0.004

0.085

Conj varY|+CT 13 0.002 0.357 0.086 0.121 Conj varY|Control 31 0.0010.229 0.086 0.056 Conj varYtop|Corpus only 10

0.796 0.089 0.249 Conj varYtop|−CT 23 0.002 1.129 0.100 0.250 ConjvarYtop|+CT 13 0.002 0.685 0.111 0.212 Conj varYtop|Control 31 0.0010.491 0.046 0.097 Conj varYrit|Corpus only 10 0.002

0.028 0.042 Conj varYrit|−CT 23 0.001 0.358

0.088 Conj varYrit|+CT 13 0.001 0.246 0.059 0.078 Conj varYrit|Control31 0.001

0.032 0.099 Conj varYbet|Corpus only 10 0.000 0.270 0.031 0.084R.varTotal|+CT 13 0.039 2.894 0.820 0.831 R.varTotal|Control 31 0.0281.365 0.312 0.371 Conj varYbot|−CT 23 0.000 0.962 0.068 0.203 ConjvarYbot|+CT 12 0.001 0.410 0.039 0.119 Conj varYbot|Control 31 0.0000.149 0.013 0.028 Conj varYlef|Corpus only 10 0.000 0.037 0.011 0.012Conj varYlef|−CT 23 0.001 1.396

0.289 Conj varYlef|+CT 12 0.002 0.441 0.065 0.126 Conj varYlef|Control31 0.000 0.036 0.006 0.008 Conj totVar|Corpus only 10 0.003 0.133 0.0410.049 Conj totVar|−CT 23 0.006 0.885

0.247 Conj totVar|+CT 13 0.003

0.166 0.222 Conj totVar|Control 31 0.003 0.272 0.046 0.065 ConjCorrXY|Corpus only  8 -0.187 0.364 0.082 0.226 Conj CorrXY|−CT 19 -0.7110.314 -0.009 0.286 Conj CorrXY|+CT 12 -0.252 0.090

0.085 Conj CorrXY|Control 30 -0.884 0.621 -0.032 0.321 ConjCorrXYtop|Corpus only  4 -0.330 0.886 0.238 0.536 Conj CorrXYtop|−CT 10-0.956 0.935 0.105 0.628 Conj CorrXYtop|+CT  3 -0.228 0.103 -0.053 0.166Conj CorrXYtop|Control 23 -0.803 0.820 0.086 0.545 Conj CorrXYrit|Corpusonly  4 -0.506 0.686 -0.020 0.505 Conj CorrXYrit|−CT 10 -0.834 0.535-0.328 0.424 Conj CorrXYrit|+CT  2

0.338 0.247 0.128 Conj CorrXYrit|Control 23 -0.982 0.827 -0.288 0.492Conj CorrXYbot|Corpus only  4 -0.691 0.429 0.017 0.493 ConjCorrXYbot|−CT  7

0.672 Conj CorrXYbot|+CT  3 -0.264 0.621 0.234 0.453 ConjCorrXYbot|Control 24 -0.948 0.957 -0.152 0.627 Conj CorrXYlef|Corpusonly  4 -0.553 0.129 -0.162 0.289 Conj CorrXYlef|−CT  9 -0.708 0.7400.098 0.620 Conj CorrXYlef|+CT  3 -0.210 0.613 0.243 0.417 ConjCorrXYlef|Control 24 -0.828 0.942 0.078 0.620 ConjvarXtopbotRatio|Corpus 10 0.132 20.331 4.889 6.923 only ConjvarXtopbotRatio|−CT 23 0.105 20.328 3.739

Conj varXtopbotRatio|+CT 12 0.052 13.072 2.187 3.684 ConjvarXtopbotRatio|Control 31 0.272 23.203 5.694 7.098 ConjvarYtopbotRatio|Corpus 10 0.036 86.220 14.147 26.741 only ConjvarYtopbotRatio|−CT 23 0.072 29.052 4.674 7.287 Conj varYtopbotRatio|+CT12 0.258 21.781 3.156 6.004 Conj varYtopbotRatio|Control 31 0.099 62.9849.846 15.751 Conj varXlefritRatio|Corpus 10 0.033 7.522 1.382 2.198 onlyConj varXlefritRatio|−CT 23 0.027 5.017 1.176 1.584 ConjvarXlefritRatio|+CT 12 0.073 6.814 1.991 2.408 ConjvarXlefritRatio|Control 31 0.031 5.415 0.999 1.348 ConjvarYlefritRatio|Corpus 10 0.138 3.160 0.898 0.909 only ConjvarYlefritRatio|−CT 23 0.092 49.468 3.009 10.185 ConjvarYlefritRatio|+CT 12 0.227 7.013 1.716 1.899 ConjvarYlefritRatio|Control 31 0.015 3.351 1.011 1.033

indicates data missing or illegible when filed

Table 5 provides p-values. Ten of the 51 measured parametersdemonstrated statistically significant differences between negativecontrols (either normal healthy people, or corporally injured but notbrain injured controls) and both positive controls (structurally braininjured) and non-structurally brain injured people. 8 additionalparameters showed statistically significant differences between negativecontrols (healthy normal people and corporally injured trauma patients)and patients with either structural or non-structural brain injury. 10of the eye tracking measures showed statistically significantcorrelation between SCAT or SAC scores, suggesting that these eyetracking parameters correlated with a validated clinical outcomemeasure.

These data demonstrate the usefulness of these mathematical algorithmsto detect and quantitate the extent of structural and non-structuralbrain injury.

Example 5 Background

Assessment of binocular gaze conjugacy in primates for research purposesis performed with the magnetic search coil technique requiring coilsimplanted into the bulbar conjunctiva (Schultz et al., “Short-termsaccadic adaptation in the macaque monkey: a binocular mechanism,”20130116 DCOM-201306262). This technique was first described by Fuchsand Robinson in 1966 and can also be performed in humans fitted withsclera search coils designed specifically for tracking eye movements(Fuchs et al., “A method for measuring horizontal and vertical eyemovement chronically in the monkey,” 19661128 DCOM-19661128).

Experimentally, spatially calibrated eye movement tracking using theBouis oculometer, which requires that the head is rigidly fixed, showsthat healthy 7-year-old children have increased disconjugacy of eyemovement during saccades relative to adults while both perform a readingtask (Bouis et al., “An accurate and linear infrared oculometer,”19831220 DCOM-19831220; Bucci et al., “Binocular coordination ofsaccades in 7 years old children in single word reading and targetfixation,” 20051219 DCOM-20060629). Research on disconjugacy duringreading can be performed using a dichoptic apparatus in which theindividual eyes are spatially calibrated independently, and presentedwith stimuli to assess movements separately for simultaneous comparisonto each other (Schotter et al., “Binocular coordination: readingstereoscopic sentences in depth,” 20120504 DCOM-20120913).

A novel eye movement tracking algorithm that appears useful forquantitating gaze conjugacy, and thus disconjugacy was developed bycomparing the positions of the right and left pupils over time as avideo is played. 22 unique subjects aged 23 to 51 (mean 32.82±7.95,median 30.5; 95.45% female) who denied neurologic disease, recenttrauma, or known ocular motility dysfunction, were presented withseveral stimuli. Stimulus 1 consisted of a music video playingcontinuously inside an aperture that moved around the perimeter of arectangular monitor. Stimulus 2 consisted of a 580 second stimulus. Thefirst 220 seconds consisted of a music video playing inside an aperturemoving in a circle. This was followed by a 45 second English textreading task and then a mixed saccade task (pro-saccades andanti-saccades) for 295 seconds. The subjects were binocularly eyetracked from a camera placed at a fixed distance. Tracking was doneusing either a portable eye tracking camera mounted on a rolling cart,or a stationary eye tracking camera at a fixed distance. Right and lefteye positions were compared to assess conjugacy of eye movement as themusic video moved relative to time. The position of each pupil wasrecorded over time elapsed as the video traveled on its time course.This enabled detection of impaired ability to move the pupils relativeto time and therefore relative to each other. We hypothesized that allof the tasks involved, namely saccade, reading, box and circle, wouldhave the same conjugacy.

Materials and Methods

Patient Selection

Healthy subjects were employees, volunteers, visitors and patients atthe Bellevue Hospital Center and the Steven and Alexandra Cohen VeteransCenter, recruited in accordance with Institutional Review Board policy.Inclusion criteria for subjects from Bellevue Hospital Center were: age18-60 years, vision correctable to within 20/50 bilaterally, intactocular motility, and ability to provide a complete ophthalmologic,medical treatment/hospitalization and neurologic history, as well asmedications/drugs/alcohol consumed within the 24 hours prior totracking. Exclusion criteria were: history of strabismus, diplopia,palsy of cranial nerves III, IV or VI, papilledema, optic neuritis orother known disorder affecting cranial nerve II, macular edema, retinaldegeneration, dementia or cognitive impairment, hydrocephalus,sarcoidosis, myasthenia gravis, multiple sclerosis or otherdemyelinating disease, active or acute epilepsy, and stroke/hemorrhageor brain injury sufficiently significant to result in hospitalization.Subjects reporting any minor brain injury regardless of loss ofconsciousness within the previous week were also excluded. Inclusioncriteria for healthy subjects from Cohen Veterans Center were: does notmeet criteria for current or lifetime mTBI/CSI, PTSD negative forcurrent and lifetime warzone related PTSD and PTSD negative forsub-syndromal warzone related PTSD based on the DSM-V diagnosticcriteria, does not meet DSM-IV diagnostic criteria for current Axis Idisorders as indexed by the SCID-IV, and no current use of psychotropicmedication for the past 2 months. Exclusion criteria were: diagnosis ofcurrent drug use disorder at the moderate or severe level as indicatedby DSMV, lifetime history of any psychiatric disorder with psychoticfeatures, bipolar I & II disorder, major depression with psychoticfeatures (including partial remission) or obsessive-compulsive disorderprior to trauma exposure, depression due to GMC involving endocrinediseases, current exposure to recurrent trauma or exposure to atraumatic event within the past 3 months, prominent suicidal orhomicidal ideation, active suicide attempt within the past 3 months,neurologic disorder or systemic illness affecting CNS function and majormedical illness (i.e. cancer, infectious ds., HIV).

Visual Stimuli

Subjects' eye movements were recorded with an Eyelink 1000 eye trackerat a fixed distance of 55 cm from a computer monitor over a time periodof 580 seconds and 220 seconds for two stimuli. For the stationarytracker the subject was seated in an adjustable height chair, using anadjustable height chinrest. Portable tracker subjects were seated ineither a height adjustable or height-fixed chair, with the monitorheight adjusted to the subject. The portable tracker chinrest wasattached to the monitor, while the stationary tracker chinrest wasattached to the same table as the computer monitor.

The stimuli were presented in series. The first stimulus involved thebox task and the second involved the circle, reading and saccade tasks.The visual stimulus contained Shakira's “Waka Waka” music video. For thebox task, the video was played continuously in a square aperture with anarea approximately ⅛ the screen size. The aperture remained stationaryat the upper left corner of the monitor screen for the first 10 secondsthen moved clockwise along the outer edge of a 17-inch diameter monitorfor five complete cycles of 40 seconds each, followed by an extra 10seconds at the end of the last cycle.

The circle task consisted of a circular aperture approximately ⅛ thescreen size in which the video played continuously as the aperture movedin a circular trajectory around the center of the monitor at a fixedspeed.

The reading task consisted of reading a few lines of instructional textfor the saccade task that immediately followed. The reading task was 45seconds in duration. 2-4 lines of text were presented every 9-10 secondsso that there was sufficient time to completely read the text, even forslow readers.

The next 295 seconds involved a saccade/anti-saccade task where twoframes were presented in pseudo-random mirrored locations around acircle. The subject was instructed to execute a pro-saccade to thesalient stimulus (frame from music video) if the cue was a green box. Ifthe cue was a red circle, the subject was instructed to inhibit thereflexive pro-saccade and execute an anti-saccade to the non-salientstimulus (pixilated color swatch). This distracter stimulus was the sameframe from the music video but randomly pixilated to maintain constantluminance and color. This well-established anti-saccade task challengescognitive processes involved in working memory, attention and responseinhibition.

The first 10 seconds of each data set were discarded in the stimulus toremove any noise that could have been recorded in the initial stage.Each stimulus was presented and eye tracked binocularly. Subjects werenot spatially calibrated to the tracker to enable independent analysisof each pupil position over time.

Data Analysis

The eye tracker sampled pupil position at 500 Hz, yielding 100,000samples over 200 seconds and 290,000 samples over 580 seconds. Comparingthe movement of one eye of a subject to the other eye of a subject wasperformed by comparing the x, y Cartesian coordinates at any time pointt. For example, by subtracting the x-coordinate of the left eye from thex-coordinate of the right eye or vice versa. Also, by subtracting they-coordinate of the left eye from the y-coordinate of the right eye orvice versa. The sum of the differences between all of the x-coordinatesover the time tested, gives us information regarding the horizontalmovement of the pupil. The sums of the differences in y-coordinates overtime gives us information regarding vertical movement of the pupil. Thetotal sum of the differences between both x- and y-coordinates over thetime tested can be summed to obtain a measure of total disconjugacy ofgaze, or calculated as an average of five trajectory cycles. In caseswhere a subject's data was missing at any given time point in the fivecycles, the denominator of the equation was the number of cycles wherethe data was present. The difference in the x- and y-position, for theleft and right eye, could then be computed. This vector of differencecould then be plotted graphically for purposes of assessment andinterpretation. To have a single metric expressing the level of pupildisconjugacy, a variance of the data may be computed with respect to anexpected mean of zero. This is significant because the code assumes thata healthy subject has zero vertical or horizontal pupil positiondifference between each eye. The variance for either horizontal (x) orvertical (substitute y for x) movement may be computed as follows:

${Var}_{x} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}\; \left( {\left( {X_{{Avg},{i\; 1}} - X_{{Avg},{i\; 2}}} \right) - 0} \right)^{2}}}$

The total variance in both the horizontal and vertical planes may becomputed as follows:

Var_(Tot)−Var_(X)+Var_(Y)

The variance in X, Y, and the total variance may be plotted in order toassess the amount of disconjugacy present in a subject. Statistics wereevaluated using MATLAB. A linear regression between X-Variable andY-Variable was calculated. A Wilcoxon's Signed Rank Sum Test was used tocheck if two variables' medians under comparison are statisticallysignificantly different.

Results

The results obtained from the subjects is provided below in Table 6.

TABLE 6 Comparison p-Value Result Conclusion Saccade X vs. Y 0.0392Reject X > Y Box X vs. Y 0.0003 Reject Y > X Reading X vs. Y 0.0022Reject Y > X Circle X vs. Y 0.4264 Accept X = Y Circle vs. Box 0.2768Accept Circle = Box Saccade vs. Circle 0.0014 Reject Saccade > CircleSaccade vs. Reading 0.0001 Reject Saccade > Reading Saccade vs. Box0.0015 Reject Saccade > Box Circle vs. Reading 0.6849 Accept Circle =Reading Box vs. Reading 0.1396 Accept Box = Reading

In Table 6 the symbol ‘>’ is used to indicate higherdisconjugacy/variance. Reject means ‘Reject the null hypothesis’ andAccept means ‘Accept the null hypothesis’. The Null hypothesis is that Xand Y in a particular comparison are equal.

Eye movement tracking has been performed for nearly 30 years to evaluatesmooth pursuit, saccades, fixation, pupil size and other aspects of gaze(Heitger et al., “Impaired eye movements in post-concussion syndromeindicate suboptimal brain function beyond the influence of depression,malingering or intellectual ability,” 20091009 DCOM-20100203; Maruta etal., “Visual tracking synchronization as a metric for concussionscreening,” 20100708 DCOM-20101013). A novel fully automatable eyetracking technique to assess conjugacy of eye movements, which does notrequire a trained examiner or sophisticated equipment is provided andused. Instead, the pupils of subjects are tracked via camera while theywatch a computer monitor playing a music video in an aperture.

The present data compares the horizontal and vertical eye movementconjugacy of 22 subjects while they watched a variety of visual stimulion a monitor. The visual stimulus tasks included a saccade/anti-saccadetask, reading text, and watching a music video in an aperture moving inboth a circle and a rectangular box shape on the monitor screen.

Conjugacy between pairs of tasks and also X and Y conjugacy within eachtask were compared. In FIGS. 33-39, the darker line represents the nullhypothesis and the lighter line represents the best-fit line for thedata observed. The results show that the saccade task induced thehighest disconjugacy compared with the circle, reading and box tasks.The differences in disconjugacy of the latter three tasks were notstatistically significant (at a 5% significance level). For the saccadestask Y conjugacy was greater than X conjugacy. For the circle, readingand box tasks, the opposite was true.

Discussion

Horizontal and vertical eye movements result from distinct and separateneural channels. Different muscles, neurons and brain stem areas areinvolved depending on whether movement is in the X- or Y-plane (Bahillet al., “Oblique saccadic eye movements. Independence of horizontal andvertical channels,” 19770812 DCOM-19770812). In humans andnon-human-primates, the six extra ocular muscles (three pairs) thatsurround the eye produce all eye movements and can rotate the eye in alldirections. The medial and lateral rectus muscles control the horizontalmovement of each eye, while the main function of the superior andinferior recti is to control the vertical movements of the eye. Thethird pair, the superior and inferior oblique muscles, contributesslightly to horizontal and vertical eye movement (Zigmond et al.,Fundamental Neuroscience, 1 ed: Elsevier Science & Technology Books,1998). These three muscle pairs are innervated by cranial nerves III,IV, and VI. Cranial nerve III, the oculomotor nerve, innervates thesuperior and inferior rectus, the medial rectus and the inferioroblique. Cranial nerve IV, the trochlear nerve, innervates the superioroblique muscle. Cranial nerve VI, the abducens nerve, innervates thelateral rectus. The three pairs of nuclei are distributed through thebrain stem and contain all of the oculomotor motor neurons. They areinterconnected by a pathway known as the medial longitudinal fasciculus.

Eye movement direction depends on which eye muscles are activated, andthis is controlled by the local circuit neurons in two gaze centers inthe reticular formation. For horizontal eye movement generation, thehorizontal gaze center or paramedian pontine reticular formation (PPRF)is responsible and made up of a collection of local circuit neurons nearthe midline in the pons. Vertical movements are the result of thevertical gaze center or rostral interstitial nucleus, which is locatedin the rostral part of the midbrain reticular formation (Purves et al.,“Neuroscience,” 2nd ed Sunderland (Mass.): Sinauer Associates, 1997).

Vertebrates normally show a response where both eyes are tightly yoked,(optokinetic nystagmus) when responding to movements in a large area oftheir visual field. Animals such as rabbits, primates and goldfish, showa coupling of both eyes' movements during most oculomotor behaviors.Some fish however have been observed to have independent spontaneous eyemovements in each eye (e.g. pipefish Corythoichthyes intestinalis andthe sandlance Limnichthyes fasciatus), which may be contributed todifferences in lifestyle and requirements for the oculomotor system(Fritsches et al., “Independent and conjugate eye movements duringoptokinesis in teleost fish,” 20020411 DCOM-20021004).

Ke et al. demonstrated that adult human smooth pursuit eye movementshave a directional asymmetry for conjugacy. Smooth pursuit was observedto be significantly faster and smoother in response to downward versusupward motion, regardless of upper or lower visual field. Smooth pursuitwas also more accurate and smooth in the horizontal versus verticalmotion. The findings suggested that the asymmetry may be an adaptiveresponse to visual context requirements, i.e. horizontal and downwardmotion directions are more critical to our survival (Ke et al.,“Directional asymmetries in human smooth pursuit eye movements,”20130701 DCOM-20130912). The present experimental data for the box andcircle task involved smooth pursuit. The length of each side of the boxwas identical. Though our box task combined the conjugacy results oflooking upward and downward in the Y direction, our results wereconsistent with the study by Ke et al. in that overall X conjugacy wasgreater than Y conjugacy (p-value 0.0003, FIG. 37). Interestingly, forthe circle task we found the X and Y conjugacy to be equal (FIG. 39).The result may have been affected by smooth pursuit at a constant angleinstead of along a vertical or horizontal plane.

Saccades involve fast eye movements that move a point of fixation intothe visual field in a conjugate manner. Horizontal saccades that becomedisconjugate may be a sign of several disorders affecting sites such asextraocular muscles and the brainstem (Serra et al., “Diagnosingdisconjugate eye movements: phase-plane analysis of horizontalsaccades,” 20081007 DCOM-20081031). These data indicate that subjectsshow significantly stronger disconjugacy during the saccades task thanwhile performing the box, circle or reading task (FIGS. 33, 34, 35, 36,37, 38 and 39). Within the saccade task, Y conjugacy was also strongerthan X conjugacy (FIG. 36). It has been observed that horizontalsaccades are faster than vertical saccades. Downward saccades have thesmallest velocities and their durations are longer (Terrybahill,Mathematical Biosciences, 1975; 27:287-298; Thomas, “The dynamics ofsmall saccadic eye movements,” 19690216 DCOM-19690216). These resultsmay suggest that a vertical, thus slower, saccade results in a higherdegree of conjugacy. If so, this would explain why Y conjugacy wasgreater in the saccades task, and also why the saccades task was moredisconjugate than tasks requiring slower smooth pursuit velocities (e.g.the box and circle tasks).

Reading involves alternating between fixations and saccadic eyemovements (Rayner, “Eye movements in reading and information processing:20 years of research,” 19981230 DCOM-19981230). The present data fromthe reading task gave us conjugacy results opposite to those of thesaccades task (FIG. 34). These data demonstrate that conjugacy wasgreater in the X direction than the Y direction during reading. GreaterX conjugacy may potentially reflect the importance of effectivehorizontal visual input on human survival from an evolutionarystandpoint, since predators and prey were more likely to be in thehorizontal than vertical plane. It should also be noted that for thereading task, the distance the eyes had to travel vertically (movingfrom one line of text to the one below) was significantly shorter thanthe distance the eyes needed to travel horizontally to read the line oftext. This may have contributed to greater X conjugacy if the overallhorizontal velocity was slower than the vertical velocity as discussedabove.

Experiments such as a box and circle task given over a larger diametercould be used to test peripheral vision. Because some of the studiescited were specific in their direction when measuring smooth pursuit,separating the up, down, left and right components of our tasks foranalysis might yield interesting results.

1. A method for localizing a central nervous system lesion in a subjectcomprising: (a) Tracking eye movement of both eyes of the subject; (b)Analyzing eye movement of both eyes of the subject; (c) Comparing eyemovement of a first eye of the subject to eye movement of a second eyeof the subject; (d) Identifying the subject as having eye movement of afirst eye that is significantly different from eye movement of a secondeye; and (e) Localizing the central nervous system lesion.
 2. A methodaccording to claim 1 wherein at least about 100,000 samples of eyeposition are obtained.
 3. A method according to claim 1 wherein eyemovement is tracked in response to a visual stimulus.
 4. A methodaccording to claim 1 wherein eye movement is tracked for a period offrom about 30 to about 500 seconds.
 5. A method according to claim 1wherein comparing eye movement of a first eye of the subject to eyemovement of a second eye of the subject is performed by generating andplotting x or y values representing a component of instantaneous angleof pupil reflection (horizontal or vertical) over a period of time.
 6. Amethod according to claim 1 wherein comparing eye movement of a firsteye of the subject to eye movement of a second eye of the subject isperformed by generating figures substantially resembling boxes thatreflect a trajectory traveled by a visual stimulation.
 7. A methodaccording to claim 1 wherein identifying the subject as having eyemovement of a first eye that is significantly different from eyemovement of a second eye comprises identifying subjects having adisconjugacy measure outlying the bell curve of normals.
 8. A method fordiagnosing a central nervous system lesion in a subject comprising: a)Tracking eye movement of both eyes of the subject; b) Analyzing eyemovement of both eyes of the subject; c) Comparing eye movement of afirst eye of the subject to eye movement of a second eye of the subject;and d) Identifying the subject as having eye movement of a first eyethat is significantly different from eye movement of a second eye.
 9. Amethod according to claim 8 wherein at least about 100,000 samples ofeye position are obtained.
 10. A method according to claim 8 wherein eyemovement is tracked in response to a visual stimulus.
 11. A methodaccording to claim 8 wherein eye movement is tracked for a period offrom about 30 to about 500 seconds.
 12. A method according to claim 8wherein comparing eye movement of a first eye of the subject to eyemovement of a second eye of the subject is performed by generating andplotting x or y values representing a component of instantaneous angleof pupil reflection (horizontal or vertical) over a period of time. 13.A method according to claim 8 wherein comparing eye movement of a firsteye of the subject to eye movement of a second eye of the subject isperformed by generating figures substantially resembling boxes thatreflect a trajectory traveled by a visual stimulation.
 14. A methodaccording to claim 8 wherein identifying the subject as having eyemovement of a first eye that is significantly different from eyemovement of a second eye comprises identifying subjects having a z-scoreabove
 2. 15. A method for detecting, diagnosing, monitoring progressionof or screening for a disease or condition featuring increasedintracranial pressure comprising: a) Tracking eye movement of both eyesof a subject; b) Analyzing eye movement of both eyes of a subject; c)Comparing eye movement of a first eye of the subject to eye movement ofa second eye of the subject; and d) Identifying the subject as havingeye movement of a first eye that is significantly different from eyemovement of a second eye.
 16. A method according to claim 15 wherein thedisease or condition featuring increased intracranial pressure isselected from the group consisting of a trauma, a cerebrovascularaccident (CVA), an aneurysm, a vascular lesion, a tumor, an infectiousprocess, an inflammatory disease, a disruption of venous drainage, apseudotumor, hydrocephalus or idiopathic.
 17. A kit useful fordiagnosing or localizing a central nervous system lesion in a subject,for detecting or screening for reduced or impaired cranial nervefunction or conduction, for detecting, diagnosing or screening forincreased intracranial pressure, or for detecting, diagnosing,monitoring progression of or screening for a disease or conditionfeaturing increased intracranial pressure comprising a device fortracking eye movement, one or more means for analyzing eye movementtracking data, and instructions.
 18. A non-transitory computer-readablemedium having instructions stored thereon for assessing a subject, theinstruction when executed by a hardware processor performing thefollowing: a) Receiving data pertaining to eye movement of the subject;b) Analyzing the eye movement data of the subject; c) Comparing eyemovement data of a first eye of the subject to eye movement data of asecond eye of the subject; and d) Identifying the subject as having eyemovement of a first eye that is significantly different from eyemovement of a second eye.
 19. A method for assessing conjugacy ordisconjugacy of eye movement in a subject comprising: a) Tracking eyemovement of both eyes of the subject; b) Analyzing eye movement of botheyes of the subject; c) Comparing the x or y Cartesian coordinates atany time point for the eye movement of a first eye of the subject to therespective x or y Cartesian coordinates at the time point for the eyemovement of a second eye of the subject; d) Providing a sum of thedifferences between all of the x coordinates of the first eye comparedto the second eye over the time tested or providing a sum of thedifferences in y coordinates of the first eye compared to the second eyeover the time tested or both; and, optionally e) Providing a total sumof the differences between both x and y coordinates of the first eyecompared to the second eye over the time tested.
 20. The methodaccording to claim 19 wherein the total sum of the differences betweenboth x and y coordinates of the first eye compared to the second eyeover the time tested is at least 50% greater than the total sum of thedifferences between x or y coordinates of the first eye compared to thesecond eye over the time tested in a healthy control or in a referencevalue based upon one or more healthy controls or based upon the subjectat a time before the time tested.
 21. The method of claim 19 wherein thetracking eye movement is performed for a total of 120 seconds or more.22. The method of claim 19 wherein 100,000 or more samples of eyeposition are obtained.
 23. The method of claim 19 wherein comparing thex or y Cartesian coordinates at any time point for the eye movement of afirst eye of the subject to the respective x or y Cartesian coordinatesat the time point for the eye movement of a second eye of the subjectcomprises plotting pairs of (x, y) values.
 24. The method of claim 19wherein providing a sum of the differences between the x or ycoordinates of the first eye compared to the second eye over the timetested or providing a sum of the differences in x or y coordinates ofthe first eye compared to the second eye over the time tested or bothcomprises calculating the total variance as follows:Var_(Tot)−Var_(x)+Var_(y).
 25. A method for diagnosing a diseasecharacterized by or featuring disconjugate gaze or strabismus in asubject comprising: a) Tracking eye movement of both eyes of thesubject; b) Analyzing eye movement of both eyes of the subject; c)Comparing the x or y Cartesian coordinates at any time point for the eyemovement of a first eye of the subject to the respective x or yCartesian coordinates at the time point for the eye movement of a secondeye of the subject; d) Providing a sum of the differences between all ofthe x coordinates of the first eye compared to the second eye over thetime tested or providing a sum of the differences in y coordinates ofthe first eye compared to the second eye over the time tested or both;and, optionally e) Providing a total sum of the differences between bothx and y coordinates of the first eye compared to the second eye over thetime tested.
 26. The method of claim 25 wherein the disease is selectedfrom the group consisting of trauma, hydrocephalus, demyelination,inflammation, infection, degenerative disease, neoplasm/paraneoplasticsyndrome, metabolic disease including diabetes, or vascular disruptionsuch as stroke, hemorrhage or aneurysm formation, and an ophthalmologicdisease.
 27. The method of claim 26 wherein the ophthalmologic diseaseis selected from the group consisting of strabismus, conjunctivitis,ophthalmoplegia, and ocular injury.
 28. A method for assessing andquantitating central nervous system integrity in a subject comprising:a) Tracking eye movement of both eyes of the subject; b) Analyzing eyemovement of both eyes of the subject; c) Comparing the x or y Cartesiancoordinates at any time point for the eye movement of a first eye of thesubject to the respective x or y Cartesian coordinates at the time pointfor the eye movement of a second eye of the subject; d) Providing a sumof the differences between all of the x coordinates of the first eyecompared to the second eye over the time tested or providing a sum ofthe differences in y coordinates of the first eye compared to the secondeye over the time tested or both; and, optionally e) Providing a totalsum of the differences between the x or y coordinates of the first eyecompared to the second eye over the time tested.
 29. A method fordetecting, monitoring progression of or screening for a disease orcondition characterized by disconjugate gaze or strabismus comprising:a) Tracking eye movement of both eyes of the subject; b) Analyzing eyemovement of both eyes of the subject; c) Comparing the x or y Cartesiancoordinates at any time point for the eye movement of a first eye of thesubject to the respective x or y Cartesian coordinates at the time pointfor the eye movement of a second eye of the subject; d) Providing a sumof the differences between all of the x coordinates of the first eyecompared to the second eye over the time tested or providing a sum ofthe differences in y coordinates of the first eye compared to the secondeye over the time tested or both; and, optionally e) Providing a totalsum of the differences between the x or y coordinates of the first eyecompared to the second eye over the time tested.
 30. The method of claim29 wherein the disease is selected from the group consisting of trauma,hydrocephalus, demyelination, inflammation, infection, degenerativedisease, neoplasm/paraneoplastic syndrome, metabolic disease includingdiabetes, or vascular disruption such as stroke, hemorrhage or aneurysmformation, and an ophthalmologic disease.
 31. The method of claim 29wherein the ophthalmologic disease is selected from the group consistingof strabismus, conjunctivitis, ophthalmoplegia, and ocular injury.
 32. Amethod for quantitating the extent of disconjugate gaze or strabismuscomprising: a) Tracking eye movement of both eyes of the subject; b)Analyzing eye movement of both eyes of the subject; c) Comparing the xor y Cartesian coordinates at any time point for the eye movement of afirst eye of the subject to the respective x or y Cartesian coordinatesat the time point for the eye movement of a second eye of the subject;d) Providing a sum of the differences between the x or y coordinates ofthe first eye compared to the second eye over the time tested orproviding a sum of the differences in the x or y coordinates of thefirst eye compared to the second eye over the time tested or both; and,optionally e) Providing a total sum of the differences between x or ycoordinates of the first eye compared to the second eye over the timetested.
 33. A kit useful for detecting, screening for or quantitatingdisconjugate gaze or strabismus, useful for diagnosing a diseasecharacterized by disconjugate gaze or strabismus in a subject, usefulfor detecting, monitoring progression of or screening for a disease orcondition characterized by disconjugate gaze or strabismus in a subjector useful for quantitating the extent of disconjugate gaze orstrabismus, containing a device for tracking eye movement comprising oneor more means for analyzing eye movement tracking data.
 34. Anon-transitory computer-readable medium having instructions storedthereon for assessing conjugacy of gaze of a subject, the instructionswhen executed by a hardware processor performing the following: a)Receiving data pertaining to eye movement of both eyes of the subject;b) Analyzing the eye movement data of both eyes of the subject; c)Comparing eye movement data of a first eye of the subject to eyemovement data of a second eye of the subject; and d) Identifying thesubject as having eye movement of a first eye that is significantlydifferent from eye movement of a second eye.
 35. A non-transitorycomputer-readable medium according to claim 16 having instructionsstored thereon for assessing conjugacy of gaze of a subject, theinstructions when executed by a hardware processor further performingthe following: a) Comparing the x or y Cartesian coordinates at any timepoint for the eye movement of a first eye of the subject to therespective x or y Cartesian coordinates at the time point for the eyemovement of a second eye of the subject; b) Providing a sum of thedifferences between all of the x or y coordinates of the first eyecompared to the second eye over the time tested or providing a sum ofthe differences in x or y coordinates of the first eye compared to thesecond eye over the time tested or both; and, optionally c) Providing atotal sum of the differences between x or y coordinates of the first eyecompared to the second eye over the time tested.
 36. A method forassessing or quantitating structural and non-structural traumatic braininjury in a subject comprising: a) Tracking eye movement of at least oneeye of the subject; b) Analyzing eye movement of at least one eye of thesubject; c) Comparing eye movement of at least one eye of the subject toa normal or mean eye movement; and, optionally d) Calculating a standarddeviation or p value for eye movement of at least one eye of the subjectas compared to the normal or mean eye movement.
 37. A method accordingto claim 36 wherein eye movement of both eyes of the subject are trackedand analyzed.
 38. A method according to claim 36 wherein x or ycoordinates of eye position for one or both eyes of a subject arecollected.
 39. A method according to claim 36 wherein the eye movementis tracked for at least about 100 or more seconds.
 40. A methodaccording to claim 36 wherein the comparing eye movement of at least oneeye of the subject to a normal or mean eye movement comprises comparingeye movement of at least one eye of the subject to the eye movement ofthe other eye of the subject or comparing eye movement of at least oneeye of the subject to the eye movement of an eye of one or more othersubjects or controls.
 41. A method according to claim 36 wherein thecomparing eye movement of at least one eye of the subject to a normal ormean eye movement comprises comparing the eye movement of both eyes ofthe subject to the eye movement of one or both eyes of one or more othersubjects or controls.
 42. A method according to claim 36 wherein thetracking, analyzing and comparing comprises collecting raw x or ycartesian coordinates of pupil position, normalizing the raw x or ycartesian coordinates, and sorting the data by eye.
 43. A methodaccording to claim 36 wherein the analyzing and comparing comprisescalculating one or more individual metric selected from the groupconsisting of $\begin{matrix}{\mspace{79mu} {{L.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (13) \\{\mspace{79mu} {{R.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (14) \\{\mspace{79mu} {{L.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (15) \\{\mspace{79mu} {{R.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (16) \\{\mspace{79mu} {{L.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (17) \\{\mspace{79mu} {{R.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (18) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (19) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (20) \\{\mspace{79mu} {{L.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (21) \\{\mspace{79mu} {{R.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (22) \\{\mspace{79mu} {{L.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (27) \\{\mspace{79mu} {{R.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (28) \\{\mspace{79mu} {{L.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (29) \\{\mspace{79mu} {{R.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (30) \\{\mspace{79mu} {{L.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (31) \\{\mspace{79mu} {{R.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (32) \\{\mspace{79mu} {{L.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (33) \\{\mspace{79mu} {{R.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (34) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (43) \\{\mspace{79mu} {{R.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (44) \\{\mspace{79mu} {{BoxHeight}_{j,k} = {\text{?} - \text{?}}}} & (45) \\{\mspace{79mu} {{BoxWidth}_{j,k} = {\text{?} - \text{?}}}} & (46) \\{\mspace{79mu} {{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}}} & (47) \\{\mspace{76mu} {{BoxArea}_{j,k} = {{BoxHeight}_{j,k} \times {BoxWidth}_{j,k}}}} & (48) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYtop}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYrit}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYbot}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYlef}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$
 44. A method according to claim 36 wherein wherein theanalyzing and comparing comprises calculating one or more individualmetric selected from the group consisting of L height, L width, L area,L varXrit, L varXlef, L varTotal, R height, R width, R area, R varYtop,R varXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, Conj varXbot,Conj varXlef and Conj varYlef.
 45. A method according to claim 36wherein the structural or non-structural traumatic brain injury isconcussion or subconcussion.
 46. A method for diagnosing a diseasecharacterized by or featuring structural and non-structural traumaticbrain injury in a subject comprising: a) Tracking eye movement of atleast one eye of the subject; b) Analyzing eye movement of at least oneeye of the subject; c) Comparing eye movement of at least one eye of thesubject to a normal or mean eye movement; and, optionally d) Calculatinga standard deviation or p value for eye movement of at least one eye ofthe subject as compared to the normal or mean eye movement.
 47. A methodaccording to claim 46 wherein eye movement of both eyes of the subjectare tracked and analyzed.
 48. A method according to claim 46 wherein xor y coordinates of eye position for one or both eyes of a subject arecollected.
 49. A method according to claim 46 wherein the eye movementis tracked for at least about 100 or more seconds.
 50. A methodaccording to claim 46 wherein the comparing eye movement of at least oneeye of the subject to a normal or mean eye movement comprises comparingeye movement of at least one eye of the subject to the eye movement ofthe other eye of the subject or comparing eye movement of at least oneeye of the subject to the eye movement of an eye of one or more othersubjects or controls.
 51. A method according to claim 46 wherein thecomparing eye movement of at least one eye of the subject to a normal ormean eye movement comprises comparing the eye movement of both eyes ofthe subject to the eye movement of one or both eyes of one or more othersubjects or controls.
 52. A method according to claim 46 wherein thetracking, analyzing and comparing comprises collecting raw x or ycartesian coordinates of pupil position, normalizing the raw x or ycartesian coordinates, and sorting the data by eye.
 53. A methodaccording to claim 46 wherein the analyzing and comparing comprisescalculating one or more individual metric selected from the groupconsisting of $\begin{matrix}{\mspace{79mu} {{L.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (13) \\{\mspace{79mu} {{R.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (14) \\{\mspace{79mu} {{L.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (15) \\{\mspace{79mu} {{R.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (16) \\{\mspace{79mu} {{L.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (17) \\{\mspace{79mu} {{R.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (18) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (19) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (20) \\{\mspace{79mu} {{L.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (21) \\{\mspace{79mu} {{R.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (22) \\{\mspace{79mu} {{L.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (27) \\{\mspace{79mu} {{R.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (28) \\{\mspace{79mu} {{L.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (29) \\{\mspace{79mu} {{R.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (30) \\{\mspace{79mu} {{L.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (31) \\{\mspace{79mu} {{R.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (32) \\{\mspace{79mu} {{L.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (33) \\{\mspace{79mu} {{R.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (34) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (43) \\{\mspace{79mu} {{R.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (44) \\{\mspace{79mu} {{BoxHeight}_{j,k} = {\text{?} - \text{?}}}} & (45) \\{\mspace{79mu} {{BoxWidth}_{j,k} = {\text{?} - \text{?}}}} & (46) \\{\mspace{79mu} {{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}}} & (47) \\{\mspace{76mu} {{BoxArea}_{j,k} = {{BoxHeight}_{j,k} \times {BoxWidth}_{j,k}}}} & (48) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYtop}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYrit}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYbot}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYlef}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$
 54. A method according to claim 46 wherein wherein theanalyzing and comparing comprises calculating one or more individualmetric selected from the group consisting of L height, L width, L area,L varXrit, L varXlef, L varTotal, R height, R width, R area, R varYtop,R varXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, Conj varXbot,Conj varXlef and Conj varYlef.
 55. A method according to claim 46wherein the structural or non-structural traumatic brain injury isconcussion or subconcussion.
 56. A method for assessing or quantitatingstructural and non-structural traumatic brain injury or diagnosing adisease characterized by or featuring structural and non-structuraltraumatic brain injury in a subject comprising: a) Tracking eye movementof at least one eye of the subject; b) Collecting raw x or y cartesiancoordinates of pupil position; c) Normalizing the raw x or y cartesiancoordinates; and d) Calculating one or more individual metric.
 57. Amethod according to claim 56 wherein eye movement of both eyes of thesubject are tracked and analyzed.
 58. A method according to claim 56wherein x or y coordinates of pupil position for both eyes of thesubject are collected.
 59. A method according to claim 56 wherein theeye movement is tracked for at least about 100 or more seconds.
 60. Amethod according to claim 56 wherein the individual metric is selectedfrom the group consisting of $\begin{matrix}{\mspace{79mu} {{L.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (13) \\{\mspace{79mu} {{R.{varYtop}} = {{Var}\left( \text{?} \right)}}} & (14) \\{\mspace{79mu} {{L.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (15) \\{\mspace{79mu} {{R.{varXrit}} = {{Var}\left( \text{?} \right)}}} & (16) \\{\mspace{79mu} {{L.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (17) \\{\mspace{79mu} {{R.{varYbot}} = {{Var}\left( \text{?} \right)}}} & (18) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (19) \\{\mspace{79mu} {{L.{varXlef}} = {{Var}\left( \text{?} \right)}}} & (20) \\{\mspace{79mu} {{L.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (21) \\{\mspace{79mu} {{R.{varTotal}} = {{Average}\mspace{11mu} \left( {{{Var}\left( \text{?} \right)} + {{Var}\left( \text{?} \right)}} \right)}}} & (22) \\{\mspace{79mu} {{L.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (27) \\{\mspace{79mu} {{R.{SkewTop}} = {{Skew}\left( \text{?} \right)}}} & (28) \\{\mspace{79mu} {{L.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (29) \\{\mspace{79mu} {{R.{SkewRit}} = {{Skew}\left( \text{?} \right)}}} & (30) \\{\mspace{79mu} {{L.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (31) \\{\mspace{79mu} {{R.{SkewBot}} = {{Skew}\left( \text{?} \right)}}} & (32) \\{\mspace{79mu} {{L.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (33) \\{\mspace{79mu} {{R.{SkewLef}} = {{Skew}\left( \text{?} \right)}}} & (34) \\{\mspace{79mu} {{L.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (37) \\{\mspace{79mu} {{R.{SkewTopNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (38) \\{\mspace{79mu} {{L.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (39) \\{\mspace{79mu} {{R.{SkewRitNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (40) \\{\mspace{79mu} {{L.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (41) \\{\mspace{79mu} {{R.{SkewBotNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (42) \\{\mspace{79mu} {{L.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (43) \\{\mspace{79mu} {{R.{SkewLefNorm}} = {{{Skew}{Norm}}\left( \text{?} \right)}}} & (44) \\{\mspace{79mu} {{BoxHeight}_{j,k} = {\text{?} - \text{?}}}} & (45) \\{\mspace{79mu} {{BoxWidth}_{j,k} = {\text{?} - \text{?}}}} & (46) \\{\mspace{79mu} {{AspectRatio}_{j,k} = \frac{{BoxHeight}_{j,k}}{{BoxWidth}_{j,k}}}} & (47) \\{\mspace{76mu} {{BoxArea}_{j,k} = {{BoxHeight}_{j,k} \times {BoxWidth}_{j,k}}}} & (48) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (57) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (58) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (59) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varXlef}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (60) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYtop}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (61) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (62) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYbot}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (63) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {varYrit}} = \frac{{\sum\; \left( \text{?} \right)^{2}} - 0}{\sum\; \text{?}}},}} & (64) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYtop}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (65) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYrit}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (66) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYbot}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}},}} & (67) \\{\mspace{79mu} {{{{Conj}\mspace{11mu} {corrXYlef}} = \frac{\sum\; \text{?}}{{\sum\; \text{?}} - 1}}{\text{?}\text{indicates text missing or illegible when filed}}}} & (68)\end{matrix}$
 61. A method according to claim 21 wherein the individualmetric is selected from the group consisting of L height, L width, Larea, L varXrit, L varXlef, L varTotal, R height, R width, R area, RvarYtop, R varXrit, R varXlef, R varTotal, Conj varX, Conj varXrit, ConjvarXbot, Conj varXlef and Conj varYlef.
 62. A method according to claim56 wherein the structural or non-structural traumatic brain injury isconcussion or subconcussion.
 63. A kit useful for detecting, screeningfor or quantitating structural and non-structural traumatic brain injuryin a subject containing a device for tracking eye movement, one or moremeans for analyzing eye movement tracking data such as, for instance, analgorithm or computer program, and instructions.
 64. A non-transitorycomputer-readable medium having instructions stored thereon forassessing or quantitating structural and non-structural traumatic braininjury or diagnosing a disease characterized by or featuring structuraland non-structural traumatic brain injury in a subject, the instructionswhen executed by a hardware processor performing the following: a)Receiving data pertaining to eye movement of one or both eyes of thesubject; b) Analyzing the eye movement data of one or both eyes of thesubject; c) Comparing eye movement data of one or both eyes of thesubject to a normal or mean eye movement; and, optionally d) Calculatinga standard deviation or p value for eye movement of one or both eyes ofthe subject as compared to the normal or mean eye movement.
 65. Anon-transitory computer-readable medium according to claim 64 havinginstructions stored thereon for quantitating structural andnon-structural traumatic brain injury or diagnosing a diseasecharacterized by or featuring structural and non-structural traumaticbrain injury in a subject, the instructions when executed by a hardwareprocessor further performing the following: a) Tracking eye movement ofat least one eye of the subject; b) collecting raw x and y cartesiancoordinates of pupil position; c) normalizing the raw x or y cartesiancoordinates; and d) calculating one or more individual metric.